Tetrahydroquinoline derivatives as p2x7 receptor antagonists

ABSTRACT

The present invention relates to tetrahydroquinoline derivatives of the present invention or a pharmaceutically acceptable salt thereof or a prodrug thereof, processes for their preparation, pharmaceutical compositions containing them and their use in the treatment of various disorders which are mediated via the P2X7 receptor.

TECHNICAL FIELD

This invention relates to tetrahydroquinoline derivatives that act asmodulators of the P2X7 receptor. The present invention also relates toprocesses for the preparation of the compounds, pharmaceuticalcompositions containing the compounds, and to their use in the treatmentof a wide range of diseases, syndromes, and disorders, which areassociated with P2X7 receptor activity such as diseases of theautoimmune and inflammatory system, diseases of the nervous andneuro-immune system, diseases involved with neuroinflammation of theCentral Nervous System (CNS) or diseases of the cardiovascular,metabolic, gastrointestinal and urogenital systems.

BACKGROUND ART

The P2X7 receptors (P2RX7) belong to the family of P2X ionotropicreceptors that are activated by extracellular nucleotides, in particularadenosine triphosphate (ATP). P2X7 receptor is distinguished from otherP2X family members by the high concentrations (mM range) of ATP requiredto activate it and by its ability to form a large pore upon prolonged orrepeated stimulation (NPL 1 to NPL 3: North, R. A., Physiol. Rev. 2002,82(4), 1013-67; Surprenant, A., Rassendren, F. et al., Science 1996,272(5262), 735-8; Virginio, C., MacKenzie, A. et al., J. Physiol., 1999,519, 335-46). The P2X7 receptor is a ligand-gated ion channel and ispresent on a variety of cell types, largely those known to be involvedin the inflammatory and/or immune process, specifically, macrophages andmonocytes in the periphery and predominantly in glial cells (microgliaand astrocytes) of the CNS. (NPL 4 to NPL 6: Duan and Neary, Glia 2006,54, 738-746; Skaper et al, FASEB J 2009, 24, 337-345; Surprenant andNorth, Annu. Rev. Physiol. 2009, 71, 333-359).

P2X7 receptor is located on many cell types, especially ones known to beinvolved in inflammatory and immune processes. Activation of the P2X7receptor by extracellular nucleotides, in particular adenosinetriphosphate, leads to the release of proinflammatory cytokines IL-1beta and IL-18 (NPL 7: Muller, et al., Am. J. Respir. Cell Mol. Biol.2011,44, 456-464), giant cell formation (macrophages/microglial cells),degranulation (mast cells) and L-selectin shedding (lymphocytes) (NPL 8to NPL 9: Ferrari et al., J. Immunol. 2006, 176, 3877-3883; Surprenantand North, Annu. Rev. Physiol. 2009, 71, 333-359). P2X7 receptors arealso located on antigen-presenting cells (keratinocytes, salivary acinarcells (parotid cells)), hepatocytes, erythrocytes, erythroleukaemiccells, monocytes, fibroblasts, bone marrow cells, neurones, and renalmesangial cells.

The importance of P2X7 in the nervous system arises primarily fromexperiments using P2X7 knockout mice. These mice demonstrate the role ofP2X7 in the development and maintenance of pain, as these mice areprotected from the development of both adjuvant-induced inflammatorypain and partial nerve ligationinduced neuropathic pain (NPL 10:Chessell et al., Pain 2005, 114, 386-396). In addition, P2X7 knockoutmice also exhibit an anti-depressant phenotype based on reducedimmobility in forced swim and tail suspension tests (NPL 11: Basso etal., Behav. Brain Res. 2009, 198, 83-90). Moreover, the P2X7 pathway islinked to the release of the proinflammatory cytokine, IL-1 beta, whichhas been linked to precipitation of mood disorders in humans (NPL 12 toNPL 13: Dantzer, Immunol. Allergy Clin. North Am. 2009, 29, 247-264;Capuron and Miller, Pharmacol. Ther. 2011, 130, 226-238). In addition,in murine models of Alzheimer's disease, P2X7 was upregulated aroundamyloid plaques indicating a role of this target in such pathology aswell (NPL 14: Parvathenani et al., J. Biol. Chem. 2003, 278,13309-13317).

There is therapeutic rationale for the use of P2X7 ion channel blockersin the treatment of a variety of disease states. These include but arenot limited to diseases associated with the central nervous system suchas stroke or injury and diseases associated with neuro-degeneration andneuroinflammation such as Alzheimer's disease, Huntington's disease,epilepsy, Amyotrophic lateral sclerosis, acute spinal cord injuryadditionally to meningitis, sleep disorders, mood and anxiety disordersas well as chronic and neuropathic and inflammatory pain. Furthermore,peripheral inflammatory disorders and autoimmune diseases including butnot limited to rheumatoid arthritis, osteoarthritis, psoriasis, allergicdermatitis, asthma, chronic obstructive pulmonary disease, airwayshyper-responsiveness, septic shock, bronchitis, glomerulonephritis,irritable bowel disease, skin injury, lung emphysema, Limb girdledystrophy type 2B, fibrosis, Syndrome of synovitis Acne Pustulosis,atherosclerosis, burn injury, spinal cord injury, Hyperostosis Osteitis,Crohn's disease, ulcerative colitis, growth and metastases of malignantcells, myoblastic leukaemia, diabetes, trauma, meningitis, osteoporosis,burn injury, ischemic heart disease, and varicose veins and trauma, areall examples where the involvement of P2X7 channels has been implicated.In addition, a recent report suggests a link between P2X7 receptor andchronic, inflammatory and neuropathic pain (NPL 15: Chessell, I. P.,Hatcher, J. P. et al., Pain, 2005, 114(3), 386-96). Overall, thesefindings indicate a role for the P2X7 receptor in the process ofneuronal synaptic transmission and therefore a potential role for P2X7antagonists as novel therapeutic tools to treat neuropathic pain.

In view of the above observations, there is significant requirement forP2X7 antagonists that can be efficiently used in the treatment of a widerange of diseases, syndromes, and disorders, which are associated withP2X7 receptor activity such as diseases of the autoimmune andinflammatory system, diseases of the nervous and neuro-immune system,diseases involved with neuroinflammation of the CNS or diseases of thecardiovascular, metabolic, gastrointestinal and urogenital systems.

Several reviews on small molecule inhibitors of P2X7 which have beenpublished are: NPL 16: Guile, S. D., et al., J. Med. Chem, 2009, 52,3123-3141; and NPL 17: Gunosewoyo, H. and Kassiou, M., Exp Opin, 2010,20, 625-646.

International patent application PTL 1: WO 2013/108227 purportedlydescribes aza-bicyclic pyridine derivatives as a P2X7 receptorantagonist. The chemical structures are dihydrofuropyridine derivativesand dihydropyranopyridine derivatives, which are quite different fromtetrahydroquinoline derivatives of the present invention. They neitherdisclose nor suggest teterhydroquinoline derivatives.

Recently, PTL 2: WO 2016/039983 and PTL3: WO 2016/019228 also discloseazabicyclic compounds with P2X7 receptor antagonistic activities. Eachchemical structure is triazolopyrazine derivative and indolizinederivative, respectively, which is quite different from atetrahydroquinoline derivative of the present invention.

CITATION LIST Patent Literature

-   {PTL 1} WO 2013/108227-   {PTL 2} WO 2016/039983-   {PTL 3} WO 2016/019228

Non Patent Literature

-   {NPL 1} North, R. A., Physiol. Rev. 2002, 82(4), 1013-67-   {NPL 2} Surprenant, A., Rassendren, F. et al., Science 1996,    272(5262), 735-8-   {NPL 3} Virginio, C., MacKenzie, A. et al., J. Physiol., 1999, 519,    335-46-   {NPL 4} Duan and Neary, Glia 2006, 54, 738-746-   {NPL 5} Skaper et al, FASEB J 2009, 24, 337-345-   {NPL 6} Surprenant and North, Annu. Rev. Physiol. 2009, 71, 333-359-   {NPL 7} Muller, et al. Am. J. Respir. Cell Mol. Biol. 2011, 44,    456-464-   {NPL 8} Ferrari et al., J. Immunol. 2006, 176, 3877-3883-   {NPL 9} Surprenant and North, Annu. Rev. Physiol. 2009, 71, 333-359-   {NPL 10} Chessell et al., Pain 2005, 114, 386-396-   {NPL 11} Basso et al., Behav. Brain Res. 2009, 198, 83-90-   {NPL 12} Dantzer, Immunol. Allergy Clin. North Am. 2009, 29, 247-264-   {NPL 13} Capuron and Miller, Pharmacol. Ther. 2011, 130, 226-238-   {NPL 14} Parvathenani et al., J. Biol. Chem. 2003, 278, 13309-13317-   {NPL 15} Chessell, I. P., Hatcher, J. P. et al., Pain, 2005, 114(3),    386-96-   {NPL 16} Guile, S. D., et al., J. Med. Chem, 2009, 52, 3123-3141-   {NPL 17} Gunosewoyo, H. and Kassiou, M., Exp Opin, 2010, 20, 625-646

SUMMARY OF INVENTION Technical Problem

There is a need in the art for P2X7 antagonists that can be used totreat a disease, syndrome, or condition in a mammal including human,wherein the disease, syndrome, or condition is affected by themodulation of P2X7 receptors, such as diseases of the autoimmune andinflammatory system; diseases of the nervous and neuro-immune system;diseases involved with, and without, neuroinflammation of the CNS;diseases of the cardiovascular, metabolic, gastrointestinal andurogenital systems; skeletal disorders, diseases involving the secretoryfunction of exocrine glands and glaucoma, Glomerulonephritis, Chaga'sDisease, chlamydia, neuroblastoma, Tuberculosis, Polycystic KidneyDisease, cancer, and acne.

It is an objective of the invention to provide new P2X7 receptorantagonists that are good drug candidates. P2X7 antagonists should bewell absorbed from the GI tract and should be metabolically stable andpossess favorable pharmacokinetic properties. They should be non-toxic.Furthermore, the ideal drug candidate would exist in a physical formthat is stable, non-hygroscopic and easily formulated. In particular, ithas been desired that compounds would have to bind potently to the P2X7receptor and show functional activity as antagonists. Also it has beendesired that compounds would have favorable pharmacokinetic properties.

Solution to Problem

With respect to other compounds disclosed in the art, the compounds ofthe present invention may show less toxicity, good absorption anddistribution, good solubility, less plasma protein binding, lessdrug-drug interaction, good metabolic stability. The present inventionprovides novel compounds which have excellent P2X7 antagonisticactivities as well as excellent pharmacokinetic properties.

In addition, the tetrahydroquinoline derivatives of the presentinvention show an excellent selectivity for the P2X7 channel as comparedwith other P2X families, especially P2X1 channel. Involvement of P2X1against auto regulation in kidney has been reported in P2X1 antagonist(NF 279) (Purinergic Signalling (2012) 8: 375-417). Thus, selective P2X7compounds of the present invention lead to improvements in theside-effect profile.

The present invention provides the following items.

[1] A compound represented by the following formula (I):

or a prodrug thereof or a pharmaceutically acceptable salt thereof,wherein:

X is N or N-oxide;

n is 0 or 1; preferably n is 1;R¹ is selected from the group consisting of:(1) hydrogen, (2) halogen, (3) hydroxyl, (4) —NH₂, (5) —NH—C₁₋₆ alkyland (6) —S(O)_(m)—C₁₋₆ alkyl; wherein m is independently 0, 1 or 2;R² is selected from the group consisting of:(1) hydrogen, (2) halogen, (3) C₁₋₆ alkyl and (4) —O—C₁₋₆ alkyl; whereinthe C₁₋₆ alkyl or the —O—C₁₋₆ alkyl is unsubstituted or substituted withone or more substituents independently selected from the groupconsisting of: halogen, hydroxyl, —O—C₁₋₆ alkyl, —CN, —NR^(9a)R^(10a),—(C═O)—R^(9a), —(C═O)—NR^(9a)R^(10a) and —S(O)_(m)—R^(9a);wherein m is independently 0, 1 or 2;R¹ may form ═CH₂ or ═O with R²; orR¹ may form a 3 to 7 membered ring with R² which may contain one or moreindependently selected from the group consisting of: nitrogen atom,oxygen atom, sulfur atom and carbonyl group; wherein the 3 to 7 memberedring is unsubstituted or substituted one or more with C₁₋₆ alkyl;R³ is independently selected from the group consisting of:(1) hydrogen, (2) halogen, (3) C₁₋₆ alkyl and (4) —O—C₁₋₆alkyl;preferably R³ is hydrogen at 4-position against X;p is 0, 1, 2 or 3; preferably p is 0 or 1;when p is 2 or 3, each R³ is the same or different;R⁴ is selected from the group consisting of:(1) hydrogen, (2) halogen and (3) hydroxyl;R⁵ is hydrogen or C₁₋₆ alkyl;R⁶ is selected from the group consisting of:(1) hydrogen, (2) C₁₋₆ alkyl, (3) hydroxyC₁₋₆ alkyl, (4) C₁₋₆ alkoxyC₁₋₆ alkyl and (5) heterocyclyl C₁₋₆ alkyl;preferably R⁶ is selected from the group consisting of (1) hydrogen and(2) C₁₋₆ alkyl;R⁵ may form a saturated 3 to 7 membered ring with R⁶ which may contain anitrogen atom, an oxygen atom, a sulfur atom or a double bond; or asaturated or unsaturated bicyclic 9 to 10 membered ring with R⁶ whichmay contain a nitrogen atom, an oxygen atom or a sulfur atom; whereinthe saturated 3 to 7 membered ring or the saturated or unsaturatedbicyclic 9 to 10 membered ring is optionally substituted with 1 to 6substituents independently selected from the group consisting of: (1)hydroxyl, (2) halogen, (3) —O-aryl and (4) —O—C₁₋₆ alkylaryl; preferablyR⁵ may form a saturated or unsaturated bicyclic 9 to 10 membered ringwith R⁶ which may contain a nitrogen atom, an oxygen atom or a sulfuratom; wherein the saturated or unsaturated bicyclic 9 to 10 memberedring is optionally substituted with 1 to 6 substituents independentlyselected from the group consisting of: (1) hydroxyl, (2) halogen and (3)—O-aryl;R^(7a) and R^(7b) are independently selected from the group consistingof:(1) hydrogen, (2) halogen, (3) hydroxyl, (4) C₁₋₆ alkyl and (5)—NR^(9b)R^(10b);preferably R^(7a) and R^(7b) are independently selected from the groupconsisting of (1) hydrogen, (4) C₁₋₆ alkyl and (5) —NR^(9b)R^(10b);R^(7a) may form a 3 to 7 membered ring with R⁵ which may contain anitrogen atom or an oxygen atom; orR^(7a) may form a 3 to 7 membered ring with R^(7b) which may contain anitrogen atom or an oxygen atom;q is 0 or 1; preferably q is 0;R⁸ is selected from the group consisting of:(1) hydrogen, (2) C₁₋₆ alkyl, (3) —O—C₁₋₆ alkyl, (4) C₂₋₆ alkenyl, (5)C₃₋₁₀ cycloalkyl, (6) —NR^(9b)R^(10b): wherein the C₁₋₆ alkyl, the—O—C₁₋₆ alkyl, the C₂₋₆ alkenyl, the C₃₋₁₀ cycloalkyl or the—NR^(9b)R^(10b) is unsubstituted or substituted with one or moresubstituents independently selected from the group consisting of:halogen and hydroxyl; (7) heterocyclyl, (8) aryl, (9) —O—C₁₋₆ alkylaryl,(10) —O-aryl, (11) heteroaryl and (12) aryl-substituted heteroaryl:wherein the heterocyclyl, the aryl, the —O—C₁₋₆ alkylaryl, the —O-aryl,the heteroaryl or the aryl-substituted heteroaryl is unsubstituted orsubstituted with one or more substituents independently selected fromthe group consisting of: halogen, hydroxyl, —O—C₁₋₆ alkyl, —O—C₁₋₆haloalkyl, —C₃₋₇ cycloalkyl, —O—C₃₋₇ cycloalkyl, hydroxyl-C₁₋₆ alkoxy,—CN, —NR^(9b)R^(10b), —(C═O)—R^(9b), —(C═O)—NR^(9b)R^(10b),—NR^(9b)—(C═O)—R^(10b), —NR¹¹—(C═O)—NR^(9b)R^(10b),—NR^(9b)—(C═O)—OR^(10b), —NR^(9b)S(O)_(m)—R^(10b), —NR¹¹—S(O)_(m)—NR^(9b)R^(10b), —S(O)_(m)—R^(9b) and C₁₋₆ alkyl which may be substitutedone or more with halogen, hydroxyl, —O—C₁₋₆ alkyl or NR^(9b)R^(10b);wherein m is independently 0, 1 or 2;preferably R⁸ is selected from the group consisting of: (1) hydrogen,(2) C₁₋₆ alkyl, (5) C₃₋₁₀ cycloalkyl, wherein the C₁₋₆ alkyl or theC₃₋₁₀ cycloalkyl is unsubstituted or substituted with one or moresubstituents independently selected from the group consisting of:halogen and hydroxyl; (7) heterocyclyl, (8) aryl, (9) —O—C₁₋₆ alkylaryl,(10) —O-aryl, (11) heteroaryl and (12) aryl-substituted heteroaryl,wherein the heterocyclyl, the aryl, the —O—C₁₋₆ alkylaryl, the —O-aryl,the heteroaryl or the aryl-substituted heteroaryl is unsubstituted orsubstituted with one or more substituents independently selected fromthe group consisting of: halogen, hydroxyl, —O—C₁₋₆ alkyl, —O—C₁₋₆haloalkyl, —CN and C₁₋₆ alkyl which may be substituted one or more withhalogen, hydroxyl, —O—C₁₋₆ alkyl or NR^(9b)R^(10b);more preferably, R¹ is selected from the group consisting of:2,4-dichloro-3-fluorophenyl, 2-chloro-3,4-difluorophenyl,2,3,4-trifluorophenyl, 2-chloro-4-fluorophenyl, 2,4-dichlorophenyl,4-chloro-2,6-difluorophenyl, 2-chloro-4,6-difluorophenyl,2,4-dichloro-6-fluorophenyl, 2,3-dichlorophenyl,2-chloro-3-(trifluoromethyl)phenyl, 2,4-dichloro-6-(hydroxymethyl)phenyland 2-chloro-4-fluoro-6-(hydroxymethyl)phenyl;R^(9a), R^(9b), R^(10a), R^(10b) or R¹¹ is independently selected fromthe group consisting of:(1) hydrogen, (2) hydroxyl, (3) C₁₋₆ alkyl and (4) hydroxyC₁₋₆ alkyl;R^(9d) may form a 4 to 7 membered ring with R^(10d) which may containone or more independently selected from the group consisting of:nitrogen atom, oxygen atom, sulfur atom and double bond, wherein the 4to 7 membered ring is optionally substituted with 1 to 6 substituentsindependently selected from the group consisting of: (1) hydroxyl,(2) halogen, (3) C₁₋₆ alkyl and (4) —O—C₆ alkyl; R^(9b) may form a 4 to7 membered ring with R^(10b) which may contain one or more independentlyselected from the group consisting of: nitrogen atom, oxygen atom,sulfur atom and double bond, wherein the 4 to 7 membered ring isoptionally substituted with 1 to 6 substituents independently selectedfrom the group consisting of: (1) hydroxyl, (2) halogen and (3) C₁₋₆alkyl.

[2] The compound according to [1]:

or a prodrug thereof or a pharmaceutically acceptable salt thereof,

wherein:

X is N;

R⁵ is hydrogen or C₆ alkyl;

R⁶ is selected from the group consisting of:

(1) hydrogen and (2) C₆ alkyl;

R⁵ may form a saturated or unsaturated bicyclic 9 to 10 membered ringwith R⁶ which may contain a nitrogen atom, an oxygen atom or a sulfuratom; wherein the saturated or unsaturated bicyclic 9 to 10 memberedring is optionally substituted with 1 to 6 substituents independentlyselected from the group consisting of: (1) hydroxyl, (2) halogen and (3)—O-aryl;

R^(7a) and R^(7b) are independently selected from the group consistingof:(1) hydrogen, (4) C₁₋₆ alkyl and (5) —NR^(9b)R^(10b);R^(7a) may form a 3 to 7 membered ring with R⁵ which may contain anitrogen atom or an oxygen atom; orR^(7a) may form a 3 to 7 membered ring with R^(7b) which may contain anitrogen atom or an oxygen atom;R⁸ is selected from the group consisting of:(1) hydrogen, (2) C₁₋₆ alkyl, (5) C₃₋₁₀ cycloalkyl, wherein the C₁₋₆alkyl or the C₃₋₁₀ cycloalkyl is unsubstituted or substituted with oneor more substituents independently selected from the group consistingof: halogen and hydroxyl; (7) heterocyclyl, (8) aryl, (9) —O—C₁₋₆alkylaryl, (10) —O-aryl, (11) heteroaryl and (12) aryl-substitutedheteroaryl, wherein the heterocyclyl, the aryl, the —O—C₁₋₆ alkylaryl,the —O-aryl, the heteroaryl or the aryl-substituted heteroaryl isunsubstituted or substituted with one or more substituents independentlyselected from the group consisting of: halogen, hydroxyl, —O—C₁₋₆ alkyl,—O—C₁₋₆ haloalkyl, —CN and C₁₋₆ alkyl which may be substituted one ormore with halogen, hydroxyl, —O—C₁₋₆ alkyl or NR^(9b)R^(10b).[3] A compound represented by the following formula (M):

or a prodrug thereof or a pharmaceutically acceptable salt thereof,wherein:n is 0 or 1; preferably n is 1;R¹ is selected from the group consisting of:(1) hydrogen, (2) halogen, (3) hydroxyl, (4) —NH₂, (5) —NH—C₁₋₆ alkyland (6) —S(O)_(m)—C₁₋₆ alkyl;wherein m is independently 0, 1 or 2;R² is selected from the group consisting of:(1) hydrogen, (2) halogen, (3) C₁₋₆ alkyl and (4) —O—C₁₋₆ alkyl; whereinthe C₁₋₆ alkyl or the —O—C₁₋₆ alkyl is unsubstituted or substituted withone or more substituents independently selected from the groupconsisting of: halogen, hydroxyl, —O—C₁₋₆ alkyl, —CN, —NR^(9a)R^(10a),—(C═O)—R^(9a), —(C═O)—NR^(9a)R^(10a) and —S(O)_(m)—R^(9a);wherein m is independently 0, 1 or 2;R¹ may form ═CH₂ or ═O with R²; orR¹ may form a 3 to 7 membered ring with R² which may contain one or moreindependently selected from the group consisting of: nitrogen atom,oxygen atom, sulfur atom and carbonyl group; where the 3 to 7 memberedring is unsubstituted or substituted one or more with C₁₋₆ alkyl;R³ is independently selected from the group consisting of:(1) hydrogen, (2) halogen, (3) C₁₋₆ alkyl and (4) —O—C₁₋₆alkyl;preferably R³ is hydrogen at 4-position against X;p is 0, 1, 2 or 3; preferably p is 0 or 1;when p is 2 or 3, each R³ is the same or different;R⁴ is selected from the group consisting of:(1) hydrogen, (2) halogen and (3) hydroxyl;R⁵ is hydrogen or C₁₋₆ alkyl;R⁶ is selected from the group consisting of:(1) hydrogen, (2) C₁₋₆ alkyl, (3) hydroxyC₁₋₆ alkyl, (4) C₁₋₆ alkoxyC₁₋₆ alkyl and (5) heterocyclyl C₁₋₆ alkyl;preferably R⁶ is selected from the group consisting of (1) hydrogen and(2) C₁₋₆ alkyl;R⁵ may form a saturated 3 to 7 membered ring with R⁶ which may contain anitrogen atom, an oxygen atom, a sulfur atom or a double bond; whereinthe saturated 3 to 7 membered ring is optionally substituted with 1 to 6substituents independently selected from the group consisting of: (1)hydroxyl, (2) halogen, (3) —O-aryl and (4) —O—C₁_6 alkylaryl;preferably R⁵ may form a saturated 3 to 7 membered ring with R⁶ whichmay contain a nitrogen atom, an oxygen atom, a sulfur atom or a doublebond; wherein the saturated 3 to 7 membered ring is optionallysubstituted with 1 to 6 substituents independently selected from thegroup consisting of: (1) hydroxyl, (2) halogen and (3) —O-aryl;R^(9a), R^(9b), R^(10a) or R^(10b) is independently selected from thegroup consisting of:(1) hydrogen, (2) hydroxyl, (3) C₁₋₆ alkyl and (4) hydroxyC₁₋₆ alkyl;R^(9a) may form a 4 to 7 membered ring with R^(10a) which may contain anitrogen atom or an oxygen atom; wherein the 4 to 7 membered ring isoptionally substituted with 1 to 6 substituents independently selectedfrom the group consisting of: (1) hydroxyl, (2) halogen, (3) C₁₋₆ alkyland (4) —O—C₁₋₆ alkyl;R^(9b) may form a 4 to 7 membered ring with R^(10b) which may contain anitrogen atom or an oxygen atom; wherein the 4 to 7 membered ring isoptionally substituted with 1 to 6 substituents independently selectedfrom the group consisting of: (1) hydroxyl, (2) halogen and (3) C₁₋₆alkyl;R¹², R¹³, R¹⁴ and R¹⁵ are independently selected from the groupconsisting of:(1) hydrogen, (2) hydroxyl, (3) halogen, (4) C₁₋₆ alkyl, (5) —O—C₁₋₆alkyl and (6) CN; wherein the C₁₋₆ alkyl or the —O—C₁₋₆ alkyl isunsubstituted or substituted with one or more substituents independentlyselected from the group consisting of: halogen, hydroxyl, —O—C₁₋₆ alkyland NR^(9b)R^(10b); orR¹² may form a 5 to 7 membered ring with R⁵ which may contain one ormore independently selected from the group consisting of: nitrogen atomand oxygen atom.

[4] The compound according to [3]:

or a prodrug thereof or a pharmaceutically acceptable salt thereof,

wherein:

n is 1;

R¹ is hydrogen or hydroxyl;

R² is methyl which is unsubstituted or substituted with one or moresubstituents independently selected from the group consisting of:halogen, hydroxyl, —O—C₁₋₆ alkyl, —CN and —NR^(9a)R^(10a);

p is 0;

R⁴ is hydrogen or fluoro;

R⁵ and R⁶ are independently selected from the group consisting of: (1)hydrogen and (2) C₁₋₆ alkyl;

R¹², R¹³ and R¹⁴ are independently selected from the group consistingof: (1) hydrogen, (3) halogen, and (4) C₁₋₃ alkyl which may besubstituted one or more with hydroxyl;

R¹⁵ is hydrogen.

[5] A compound which is selected from the group following or a prodrugthereof or a pharmaceutically acceptable salt thereof,

N-(2,4-dichloro-6-methylbenzyl)-8-oxo-5,6,7,8-tetrahydroquinoline-5-carboxamide;

N-(2-chloro-3-(trifluoromethyl)benzyl)-8-oxo-5,6,7,8-tetrahydroquinoline-5-carboxamide;

N-(2,3-dichlorobenzyl)-8-oxo-5,6,7,8-tetrahydroquinoline-5-carboxamide;

N-(2,4-dichloro-6-(hydroxymethyl)benzyl)-8-oxo-5,6,7,8-tetrahydroquinoline-5-carboxamide;

N-(cycloheptylmethyl)-8-oxo-5,6,7,8-tetrahydroquinoline-5-carboxamide;

N-(2,4-dichloro-6-methylbenzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;

N-(2-chloro-3-(trifluoromethyl)benzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;N-(2,3-dichlorobenzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;N-(2,4-dichloro-6-(hydroxymethyl)benzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;N-(2,4-dichloro-6-(methoxymethyl)benzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;N-(2,4-dichloro-6-methylbenzyl)-7-methylene-6,7-dihydro-5H-cyclopenta[b]pyridine-5-carboxamide;N-(2,4-dichloro-6-methylbenzyl)-5-fluoro-8-oxo-5,6,7,8-tetrahydroquinoline-5-carboxamide;N-(2-chloro-3-(trifluoromethyl)benzyl)-5-fluoro-8-oxo-5,6,7,8-tetrahydroquinoline-5-carboxamide;N-(2,4-dichloro-6-(hydroxymethyl)benzyl)-5-fluoro-8-oxo-5,6,7,8-tetrahydroquinoline-5-carboxamide;N-(2,4-dichloro-6-methylbenzyl)-5-hydroxy-8-oxo-5,6,7,8-tetrahydroquinoline-5-carboxamide;N-(2,4-dichloro-6-methylbenzyl)-7-oxo-6,7-dihydro-5H-cyclopenta[b]pyridine-5-carboxamide;N-(2-chloro-3-(trifluoromethyl)benzyl)-7-oxo-6,7-dihydro-5H-cyclopenta[b]pyridine-5-carboxamide;N-(2,4-dichloro-6-methylbenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;N-(2-chloro-3-(trifluoromethyl)benzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;N-(2,4-dichloro-6-(hydroxymethyl)benzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;N-(2,3-dichlorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;N-(2,4-dichlorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;N-(2,4-dichloro-6-(methoxymethyl)benzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;N-(2,4-dichloro-6-methylbenzyl)-5,8-dihydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;N-(2-chloro-3-(trifluoromethyl)benzyl)-5,8-dihydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;N-(2,4-dichloro-6-methylbenzyl)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridine-5-carboxamide;N-(2-chloro-3-(trifluoromethyl)benzyl)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridine-5-carboxamide;N-(2,3-dichlorobenzyl)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridine-5-carboxamide;N-(2,4-dichlorobenzyl)-5-fluoro-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridine-5-carboxamide;2-(5-((2,4-dichloro-6-methylbenzyl)carbamoyl)-5,6,7,8-tetrahydroquinolin-8-yl)aceticacid;2-(5-((2-chloro-3-(trifluoromethyl)benzyl)carbamoyl)-5,6,7,8-tetrahydroquinolin-8-yl)acetic acid;(2-amino-2-oxoethyl)-N-(2-chloro-3-(trifluoromethyl)benzyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;N-(2,4-dichloro-6-methylbenzyl)-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;N-(2,4-dichloro-6-methylbenzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;N-(2-chloro-3-(trifluoromethyl)benzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;N-(2,3-dichlorobenzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;N-(2,4-dichlorobenzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;N-(2,4-dichlorobenzyl)-5-fluoro-7-hydroxy-7-(hydroxymethyl)-6,7-dihydro-5H-cyclopenta[b]pyridine-5-carboxamide;N-(2,4-dichloro-6-methylbenzyl)-5-fluoro-8-hydroxy-8-(methoxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;N-(2-chloro-3-(trifluoromethyl)benzyl)-5-fluoro-8-hydroxy-8-(methoxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S*,8S*)-N-(2,4-dichlorobenzyl)-5-fluoro-8-hydroxy-8-(methoxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S*,8S*)-N-(2-chloro-4-fluorobenzyl)-5-fluoro-8-hydroxy-8-(methoxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;8-(aminomethyl)-N-(2,4-dichloro-6-methylbenzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;N-(2,4-dichloro-6-methylbenzyl)-8-hydroxy-8-((methylamino)methyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;8-(aminomethyl)-N-(2,4-dichloro-6-methylbenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;N-(2,4-dichloro-6-methylbenzyl)-5-fluoro-8-hydroxy-8-((methylamino)methyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;N-(2,4-dichloro-6-methylbenzyl)-8-((dimethylamino)methyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;8-(aminomethyl)-N-(2-chloro-3-(trifluoromethyl)benzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;N-(2-chloro-3-(trifluoromethyl)benzyl)-5-fluoro-8-hydroxy-8-((methylamino)methyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;N-(2-chloro-3-(trifluoromethyl)benzyl)-8-((dimethylamino)methyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S*,8R*)-N-(2,4-dichlorobenzyl)-5-fluoro-8-hydroxy-8-((3-hydroxyazetidin-1-yl)methyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S*,8R*)-N-(2-chloro-4-fluorobenzyl)-5-fluoro-8-hydroxy-8-((3-hydroxyazetidin-1-yl)methyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S*,8R*)-N-(2-chloro-4-fluorobenzyl)-5-fluoro-8-hydroxy-8-((3-methoxyazetidin-1-yl)methyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S*,8R*)-N-(2-chloro-4-fluorobenzyl)-5-fluoro-8-hydroxy-8-((3-hydroxy-3-methylazetidin-1-yl)methyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S*,8R*)-N-(2-chloro-4-fluorobenzyl)-5-fluoro-8-hydroxy-8-((3-methoxy-3-methylazetidin-1-yl)methyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S*,8R*)-N-(2-chloro-4-fluorobenzyl)-5-fluoro-8-hydroxy-8-(((2-hydroxyethyl)amino)methyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S*,8R*)-N-(2-chloro-4-fluorobenzyl)-5-fluoro-8-hydroxy-8-(((2-hydroxyethyl)(methyl)amino)methyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;N-(2-chloro-3-(trifluoromethyl)benzyl)-5-fluoro-8-hydroxy-8-methyl-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S*,8R*)-8-amino-N-(2,4-dichlorobenzyl)-5-fluoro-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S*,8S*)-8-amino-N-(2,4-dichlorobenzyl)-5-fluoro-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(3R*,5'S*)-N-(2,4-dichlorobenzyl)-5′-fluoro-5-oxo-6′,7′-dihydro-5′H-spiro[morpholine-3,8′-quinoline]-5′-carboxamide;(3S*,5'S*)-N-(2,4-dichlorobenzyl)-5′-fluoro-5-oxo-6′,7′-dihydro-5′H-spiro[morpholine-3,8′-quinoline]-5′-carboxamide;(5S,8)-N-(2,4-dichloro-6-methylbenzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8S)-N-(2,4-dichloro-6-methylbenzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2,4-dichlorobenzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8S)-N-(2,4-dichlorobenzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-4-fluorobenzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8S)-N-(2-chloro-4-fluorobenzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2,4-dichloro-6-fluorobenzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8S)-N-(2,4-dichloro-6-fluorobenzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-8-hydroxy-N-(2,3,4-trifluorobenzyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8S)-8-hydroxy-N-(2,3,4-trifluorobenzyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8S)-8-hydroxy-N-(2,4,6-trifluorobenzyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8S)-N-(2,4-difluorobenzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(4-fluoro-2-(trifluoromethyl)benzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8S)-N-(4-fluoro-2-(trifluoromethyl)benzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8S)-N-(4-chloro-2-fluorobenzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8S)-N-(4-chloro-2-fluorobenzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8S)-N-(4-bromo-2-fluorobenzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8S)-N-(4-bromo-2-fluorobenzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-3,4-difluorobenzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8S)-N-(2-chloro-3,4-difluorobenzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,7S)-N-(2,4-dichloro-6-methylbenzyl)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridine-5-carboxamide;(5R,8R)-N-(2,4-dichloro-6-methylbenzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-N-(2,4-dichloro-6-methylbenzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-3-(trifluoromethyl)benzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8R)-N-(2,4-dichlorobenzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-N-(2,4-dichlorobenzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8R)-N-(2-chloro-4-fluorobenzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-N-(2-chloro-4-fluorobenzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8R)-N-(2,4-dichloro-6-fluorobenzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-N-(2,4-dichloro-6-fluorobenzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8R)-8-hydroxy-N-(2,3,4-trifluorobenzyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-8-hydroxy-N-(2,3,4-trifluorobenzyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8R)-N-(4-chloro-2-fluorobenzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-N-(4-chloro-2-fluorobenzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,7R)-N-(2,4-dichloro-6-methylbenzyl)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridine-5-carboxamide;(5S,7R)-N-(2,4-dichloro-6-methylbenzyl)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridine-5-carboxamide;(5R,8S)-N-(2,4-dichloro-6-methylbenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-N-(2,4-dichloro-6-methylbenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8S)-N-(2-chloro-3-(trifluoromethyl)benzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-N-(2-chloro-3-(trifluoromethyl)benzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8S)-N-(2,4-dichloro-6-(hydroxymethyl)benzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-N-(2,4-dichloro-6-(hydroxymethyl)benzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8S)-N-(2,4-dichlorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-N-(2,4-dichlorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-N-(2-chloro-4-fluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-5-fluoro-8-hydroxy-N-(2,3,4-trifluorobenzyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-N-(2,4-difluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-5-fluoro-N-(4-fluoro-2-(trifluoromethyl)benzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-N-(4-chloro-2-fluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8S)-N-(2,6-dichloro-4-(trifluoromethyl)benzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-N-(2,6-dichloro-4-(trifluoromethyl)benzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8S)-N-(2,4-dichloro-6-(difluoromethyl)benzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-N-(2,4-dichloro-6-(difluoromethyl)benzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8S)-N-(2,4-dichloro-6-fluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-N-(2,4-dichloro-6-fluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-N-(4-bromo-2-chlorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-N-((R)-1-(2,4-dichlorophenyl)ethyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8S)-N-(2,3-dichlorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-N-(2,3-dichlorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-N-(2-chloro-6-methylbenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-N-(2-chloro-4,5-difluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-5-fluoro-8-hydroxy-N-(2,3,6-trichlorobenzyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-N-(2-chloro-4-methylbenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8R)-N-(2,4-dichloro-6-methylbenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2,4-dichloro-6-methylbenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8R)-N-(2-chloro-3-(trifluoromethyl)benzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-3-(trifluoromethyl)benzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8R)-N-(2,4-dichloro-6-(hydroxymethyl)benzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2,4-dichloro-6-(hydroxymethyl)benzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8R)-N-(2,4-dichlorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2,4-dichlorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8R)-N-(2-chloro-4-fluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-4-fluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8R)-5-fluoro-8-hydroxy-N-(2,3,4-trifluorobenzyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-5-fluoro-8-hydroxy-N-(2,3,4-trifluorobenzyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8R)-N-(2,6-dichlorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2,6-dichlorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8R)-N-(2,4-difluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2,4-difluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-6-fluoro-3-methylbenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8R)-5-fluoro-N-(4-fluoro-2-(trifluoromethyl)benzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-5-fluoro-N-(4-fluoro-2-(trifluoromethyl)benzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8R)-N-(4-chloro-2-fluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(4-chloro-2-fluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8R)-N-(2,6-dichloro-4-(trifluoromethyl)benzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2,6-dichloro-4-(trifluoromethyl)benzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2,4-dichloro-6-(difluoromethyl)benzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-4-fluoro-6-(hydroxymethyl)benzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8R)-N-(2,4-dichloro-6-fluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2,4-dichloro-6-fluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8R)-N-(4-bromo-2-chlorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(4-bromo-2-chlorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8R)-N-((R)-1-(2,4-dichlorophenyl)ethyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8R)-N-(4-chloro-2-(trifluoromethyl)benzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(4-chloro-2-(trifluoromethyl)benzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8R)-N-(2,3-dichlorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2,3-dichlorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8R)-N-(2-chloro-6-methylbenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-6-methylbenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8R)-N-(2-chloro-4,5-difluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-4,5-difluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8R)-5-fluoro-8-hydroxy-N-(2,3,6-trichlorobenzyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-5-fluoro-8-hydroxy-N-(2,3,6-trichlorobenzyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8R)-N-(2-chloro-4-methylbenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-4-methylbenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-5-fluoro-8-hydroxy-N-((S)-1-(2,3,4-trichlorophenyl)ethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-3-fluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-3,6-difluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-6-fluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-4-methoxybenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2,5-dichlorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-3,4-difluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-5-fluoro-N-(2-fluoro-3-(trifluoromethyl)benzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-4,6-difluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-((3,5-dichloropyridin-2-yl)methyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-5-fluoro-N-(3-fluoro-2-(trifluoromethyl)benzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-6-(trifluoromethyl)benzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-5-fluoro-8-hydroxy-N-(2,4,6-trifluorobenzyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(5-bromo-2-chlorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(4-bromo-2-fluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(4-chloro-2,3-difluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(4-chloro-2,6-difluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(3-chloro-2,4-difluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-5-fluoro-N-(2-fluoro-6-(trifluoromethyl)benzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-4-(trifluoromethyl)benzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(3-chloro-4-fluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-5-fluoro-8-hydroxy-N-((R)-1,2,3,4-tetrahydronaphthalen-1-yl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(3-chloro-2-fluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2,4-dichlorophenethyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-5-fluoro-8-hydroxy-N-((1-morpholinocyclohexyl)methyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(3-chloro-2,6-difluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-((3-chloro-5-(trifluoromethyl)pyridin-2-yl)methyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chlorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-((R)-2,3-dihydro-1H-inden-1-yl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(3,4-dichlorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-6-methoxybenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-5-fluoro-8-hydroxy-N-(2-(trifluoromethyl)benzyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-5-fluoro-8-hydroxy-N-(3,4,5-trifluorobenzyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(4-cyano-2-fluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(3,4-difluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(3-chloro-5-fluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide(5S,8S)-N-(2-chloro-5-fluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(3-chlorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(4-chloro-3-fluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-5-fluoro-N-(2-fluoro-4-(trifluoromethoxy)benzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2,3-difluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-5-(trifluoromethyl)benzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(4-chlorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-5-fluoro-8-hydroxy-N-(4-methoxy-2-(trifluoromethyl)benzyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(3,5-dichlorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-((4-(4-chlorophenyl)thiazol-2-yl)methyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-5-fluoro-8-hydroxy-N-(2-(morpholinomethyl)benzyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-5-fluoro-8-hydroxy-N-((1S,2R)-2-phenylcyclopropyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(6-chloro-2-fluoro-3-methylbenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2,6-difluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-5-fluoro-8-hydroxy-N-((S)-1,2,3,4-tetrahydronaphthalen-1-yl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-5-fluoro-8-hydroxy-N-(2-(3-(trifluoromethyl)phenoxy)ethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-5-fluoro-N-((1-(4-fluorophenyl)cyclopropyl)methyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(3,5-difluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-5-fluoro-8-hydroxy-N-((1R,2S)-2-phenylcyclopropyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-5-fluoro-N-(2-fluorobenzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-3-methoxybenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-((S)-2,3-dihydro-1H-inden-1-yl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(3,3-dimethylbutyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-5-fluoro-8-hydroxy-N-(2-phenoxyethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(4,6-dichloro-2,3-dihydrobenzofuran-3-yl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(5,7-dichlorochroman-4-yl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(1-(adamantan-1-yl)ethyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-(4-chlorophenyl)-2-(4,4-difluoropiperidin-1-yl)ethyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(chroman-3-yl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-(4-chlorophenyl)propyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-5-fluoro-8-hydroxy-N-(2-morpholino-2-phenylethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-(4,4-difluoropiperidin-1-yl)-2-(4-methylthiazol-5-yl)ethyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-((R)-1-(2-chloro-4-fluorophenyl)ethyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-((trans)-2-(2,4-dichlorophenyl)cyclopropyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-((S)-1-(2-chloro-4-fluorophenyl)ethyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-((4-(2,4-dichlorophenyl)tetrahydro-2H-pyran-4-yl)methyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2,4-dichlorobenzyl)-3,5-difluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-4-fluorobenzyl)-3,5-difluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2,4-dichlorobenzyl)-5-fluoro-8-hydroxy-3-methyl-5,6,7,8-tetrahydroquinoline-5-carboxamide(5S,8S)-N-(2-chloro-4-fluorobenzyl)-5-fluoro-8-hydroxy-3-methyl-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-5-((2,4-dichlorobenzyl)carbamoyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline1-oxide;(R)-N-(2-chloro-3-(trifluoromethyl)benzyl)-5-fluoro-8-oxo-5,6,7,8-tetrahydroquinoline-5-carboxamide;(S)-N-(2-chloro-3-(trifluoromethyl)benzyl)-5-fluoro-8-oxo-5,6,7,8-tetrahydroquinoline-5-carboxamide;(S)-N-(2,4-dichlorobenzyl)-5-fluoro-8-oxo-5,6,7,8-tetrahydroquinoline-5-carboxamide;(S)-N-(2-chloro-4-fluorobenzyl)-5-fluoro-8-oxo-5,6,7,8-tetrahydroquinoline-5-carboxamide;(S)-N-(2-chloro-3-fluorobenzyl)-5-fluoro-8-oxo-5,6,7,8-tetrahydroquinoline-5-carboxamide;(S)-N-(2,4-dichloro-6-fluorobenzyl)-5-fluoro-8-oxo-5,6,7,8-tetrahydroquinoline-5-carboxamide;(S)-N-(2,3-dichlorobenzyl)-5-fluoro-8-oxo-5,6,7,8-tetrahydroquinoline-5-carboxamide;(S)-N-(2-chloro-4-(trifluoromethyl)benzyl)-5-fluoro-8-oxo-5,6,7,8-tetrahydroquinoline-5-carboxamide;(S)-5-fluoro-8-oxo-N-(2,3,4-trifluorobenzyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(S)-N-((3,5-dichloropyridin-2-yl)methyl)-5-fluoro-8-oxo-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2,4-dichlorobenzyl)-5-fluoro-8-hydroxy-8-methyl-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-N-(2,4-dichlorobenzyl)-5-fluoro-8-hydroxy-8-methyl-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-5-fluoro-8-hydroxy-8-methyl-N-(2,3,4-trifluorobenzyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-4-fluorobenzyl)-5-fluoro-8-hydroxy-8-methyl-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-N-(2-chloro-4-fluorobenzyl)-5-fluoro-8-hydroxy-8-methyl-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2,4-dichloro-6-(hydroxymethyl)benzyl)-5-fluoro-8-hydroxy-8-methyl-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-4-fluoro-6-(hydroxymethyl)benzyl)-5-fluoro-8-hydroxy-8-methyl-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2,4-difluorobenzyl)-5-fluoro-8-hydroxy-8-methyl-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(4-chloro-2-fluorobenzyl)-5-fluoro-8-hydroxy-8-methyl-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2,4-dichloro-6-fluorobenzyl)-5-fluoro-8-hydroxy-8-methyl-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-4,6-difluorobenzyl)-5-fluoro-8-hydroxy-8-methyl-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(4-chloro-2,3-difluorobenzyl)-5-fluoro-8-hydroxy-8-methyl-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(3-chloro-2,4-difluorobenzyl)-5-fluoro-8-hydroxy-8-methyl-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(4-chloro-2,6-difluorobenzyl)-5-fluoro-8-hydroxy-8-methyl-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-((R)-1-(2-chloro-4-fluorophenyl)ethyl)-5-fluoro-8-hydroxy-8-methyl-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-((S)-1-(2-chloro-4-fluorophenyl)ethyl)-5-fluoro-8-hydroxy-8-methyl-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-((3,5-dichloropyridin-2-yl)methyl)-5-fluoro-8-hydroxy-8-methyl-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-((trans)-2-(2,4-dichlorophenyl)cyclopropyl)-5-fluoro-8-hydroxy-8-methyl-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-5-fluoro-8-hydroxy-8-methyl-N-((1-morpholinocyclohexyl)methyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-5-fluoro-8-hydroxy-8-methyl-N-((1-morpholinocyclohexyl)methyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-4-fluorobenzyl)-5-fluoro-8-hydroxy-3,8-dimethyl-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-N-(2,4-dichlorobenzyl)-5-fluoro-8-hydroxy-8-(((2-hydroxyethyl)(methyl)amino)methyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8S)-N-(2,4-dichlorobenzyl)-5-fluoro-8-hydroxy-8-(((2-hydroxyethyl)(methyl)amino)methyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8S)-N-(2,4-dichlorobenzyl)-5-fluoro-8-hydroxy-8-((3-hydroxyazetidin-1-yl)methy1)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-8-(cyanomethyl)-N-(2,4-dichlorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-N-(2-chloro-4-fluorobenzyl)-8-(cyanomethyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-4-fluorobenzyl)-8-(cyanomethyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-8-(cyanomethyl)-N-(2,4-dichloro-6-(hydroxymethyl)benzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-N-(2-chloro-4-fluoro-6-(hydroxymethyl)benzyl)-8-(cyanomethyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2,4-dichlorobenzyl)-5-fluoro-8-(fluoromethyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-4-fluorobenzyl)-5-fluoro-8-(fluoromethyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2,4-dichlorobenzyl)-5-fluoro-8-hydroxy-8-((methylthio)methyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-4-fluorobenzyl)-5-fluoro-8-hydroxy-8-((methylthio)methyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-4-fluorobenzyl)-5-fluoro-8-hydroxy-8-(((2-hydroxyethyl)thio)methyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(2R,5'S)-N-(2,4-dichlorobenzyl)-5′-fluoro-4-methyl-6′,7′-dihydro-5′H-spiro[morpholine-2,8′-quinoline]-5′-carboxamide;(5S,5'S)-N-(2,4-dichlorobenzyl)-5′-fluoro-2-oxo-6′,7′-dihydro-5′H-spiro[oxazolidine-5,8′-quinoline]-5′-carboxamide;(5R,5'S)-N-(2,4-dichlorobenzyl)-5′-fluoro-2-oxo-6′,7′-dihydro-5′H-spiro[oxazolidine-5,8′-quinoline]-5′-carboxamide;(2S,5′R)-N-(2,4-dichlorobenzyl)-5′-fluoro-5-oxo-6′,7′-dihydro-5′H-spiro[morpholine-2,8′-quinoline]-5′-carboxamide;(2S,5'S)-N-(2,4-dichlorobenzyl)-5′-fluoro-5-oxo-6′,7′-dihydro-5′H-spiro[morpholine-2,8′-quinoline]-5′-carboxamide;(2R,5'S)-N-(2,4-dichlorobenzyl)-5′-fluoro-5-oxo-6′,7′-dihydro-5′H-spiro[morpholine-2,8′-quinoline]-5′-carboxamide;(5S,8S)-N-(2-chloro-4-fluorobenzyl)-5-fluoro-8-hydroxy-8-((methylsulfinyl)methyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-N-(2,4-dichlorobenzyl)-5-fluoro-8-hydroxy-8-((methylthio)methyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2,4-dichlorobenzyl)-5-fluoro-8-hydroxy-8-((methylsulfonyl)methyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-4-fluorobenzyl)-5-fluoro-8-hydroxy-8-((methylsulfonyl)methyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2,4-dichlorobenzyl)-5-fluoro-8-hydroxy-8-(((2-hydroxyethyl)sulfonyl)methyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-4-fluorobenzyl)-5-fluoro-8-hydroxy-8-(((2-hydroxyethyl)sulfonyl)methyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8R)-N-(2,4-dichlorobenzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8S)-N-(2,4-dichlorobenzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2,4-dichlorobenzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-N-(2,4-dichlorobenzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-4-fluorobenzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-N-(2-chloro-4-fluorobenzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-N-(2,3,4-trifluorobenzyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-N-(2,3,4-trifluorobenzyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2,4-dichloro-6-fluorobenzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-N-(2,4-dichloro-6-fluorobenzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-3,4-difluorobenzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-N-(2-chloro-3,4-difluorobenzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(4-chloro-2-fluorobenzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-N-(4-chloro-2-fluorobenzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2,4-dichloro-6-(hydroxymethyl)benzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-4-fluoro-6-(hydroxymethyl)benzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2,4-difluorobenzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2,4-dichloro-3-fluorobenzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2,3-dichloro-4-fluorobenzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-4,6-difluorobenzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(4-chloro-2,3-difluorobenzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(3-chloro-2,4-difluorobenzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(4-chloro-2,6-difluorobenzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2,4-dichlorobenzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-3-methyl-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-((R)-1-(2,4-dichlorophenyl)ethyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-((R)-1-(2-chloro-4-fluorophenyl)ethyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-N-((R)-1-(2-chloro-4-fluorophenyl)ethyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-((3,5-dichloropyridin-2-yl)methyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2,4-dichlorophenethyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-((trans)-2-(2,4-dichlorophenyl)cyclopropyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-((4-(2,4-dichlorophenyl)tetrahydro-2H-pyran-4-yl)methyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8S)-N-(2,4-dichloro-6-(hydroxymethyl)benzyl)-5-fluoro-8-methoxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-N-(2,4-dichloro-6-(hydroxymethyl)benzyl)-5-fluoro-8-methoxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2,4-dichloro-6-fluorobenzyl)-5-fluoro-8-methoxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2,3-dichlorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-4-fluorobenzyl)-5-fluoro-8-methoxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-4-(trifluoromethyl)benzyl)-5-fluoro-8-methoxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-5-fluoro-8-methoxy-N-(2,3,4-trifluorobenzyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(4-chloro-2-fluorobenzyl)-5-fluoro-8-methoxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-5-fluoro-8-methoxy-N-(2,4,6-trifluorobenzyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8)-N-(2,4-difluorobenzyl)-5-fluoro-8-methoxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2,4-dichloro-6-(hydroxymethyl)benzyl)-5-fluoro-8-(2-hydroxyethoxy)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-4-fluorobenzyl)-5-fluoro-8-(2-hydroxyethoxy)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-5-fluoro-8-(2-hydroxyethoxy)-N-(2,3,4-trifluorobenzyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(4-chloro-2-fluorobenzyl)-5-fluoro-8-(2-hydroxyethoxy)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2,4-difluorobenzyl)-5-fluoro-8-(2-hydroxyethoxy)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8R)-N-(2,4-dichlorobenzyl)-5-fluoro-8-(2-hydroxyethoxy)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2,4-dichlorobenzyl)-8-(2,3-dihydroxypropoxy)-5-fluoro-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8rac)-N-(2,4-dichlorobenzyl)-5-fluoro-8-(methylsulfonyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8rac)-N-(2,4-dichlorobenzyl)-5-fluoro-8-((2-hydroxyethyl)sulfonyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8S)-N-(2-chloro-3-(trifluoromethyl)benzyl)-5,8-difluoro-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8S)-N-(2,4-dichlorobenzyl)-5,8-difluoro-5,6,7,8-tetrahydroquinoline-5-carboxamideand(5R,8S)-N-(2,3-dichlorobenzyl)-5,8-difluoro-5,6,7,8-tetrahydroquinoline-5-carboxamide.

[6] The compound according to [5], which is selected from the groupfollowing or a prodrug thereof or a pharmaceutically acceptable saltthereof,

N-(2,3-dichlorobenzyl)-8-oxo-5,6,7,8-tetrahydroquinoline-5-carboxamide;

N-(2,4-dichloro-6-(hydroxymethyl)benzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;

N-(2-chloro-3-(trifluoromethyl)benzyl)-7-oxo-6,7-dihydro-5H-cyclopenta[b]pyridine-5-carboxamide;

N-(2,4-dichloro-6-methylbenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;

N-(2-chloro-3-(trifluoromethyl)benzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;

N-(2,4-dichloro-6-(hydroxymethyl)benzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;

N-(2,3-dichlorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;

N-(2,4-dichlorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;

N-(2-chloro-3-(trifluoromethyl)benzyl)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridine-5-carboxamide;

N-(2,4-dichlorobenzyl)-5-fluoro-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridine-5-carboxamide;

2-(5-((2,4-dichloro-6-methylbenzyl)carbamoyl)-5,6,7,8-tetrahydroquinolin-8-yl)aceticacid;

2-(5-((2-chloro-3-(trifluoromethyl)benzyl)carbamoyl)-5,6,7,8-tetrahydroquinolin-8-yl)acetic acid;

N-(2-chloro-3-(trifluoromethyl)benzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;

N-(2,3-dichlorobenzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;N-(2,4-dichlorobenzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;N-(2,4-dichlorobenzyl)-5-fluoro-7-hydroxy-7-(hydroxymethyl)-6,7-dihydro-5H-cyclopenta[b]pyridine-5-carboxamide;(5S*,8S*)-N-(2-chloro-4-fluorobenzyl)-5-fluoro-8-hydroxy-8-(methoxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;N-(2,4-dichloro-6-methylbenzyl)-8-((dimethylamino)methyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S*,8R*)-N-(2,4-dichlorobenzyl)-5-fluoro-8-hydroxy-8-((3-hydroxyazetidin-1-yl)methyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S*,8R*)-N-(2-chloro-4-fluorobenzyl)-5-fluoro-8-hydroxy-8-((3-hydroxyazetidin-1-yl)methyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S*,8R*)-N-(2-chloro-4-fluorobenzyl)-5-fluoro-8-hydroxy-8-((3-methoxyazetidin-1-yl)methyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S*,8R*)-N-(2-chloro-4-fluorobenzyl)-5-fluoro-8-hydroxy-8-((3-hydroxy-3-methylazetidin-1-yl)methyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S*,8R*)-N-(2-chloro-4-fluorobenzyl)-5-fluoro-8-hydroxy-8-((3-methoxy-3-methylazetidin-1-yl)methyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S*,8R*)-N-(2-chloro-4-fluorobenzyl)-5-fluoro-8-hydroxy-8-(((2-hydroxyethyl)amino)methyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S*,8R*)-N-(2-chloro-4-fluorobenzyl)-5-fluoro-8-hydroxy-8-(((2-hydroxyethyl)(methyl)amino)methyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(3R*,5'S*)-N-(2,4-dichlorobenzyl)-5′-fluoro-5-oxo-6′,7′-dihydro-5′H-spiro[morpholine-3,8′-quinoline]-5′-carboxamide;(3S*,5'S*)-N-(2,4-dichlorobenzyl)-5′-fluoro-5-oxo-6′,7′-dihydro-5′H-spiro[morpholine-3,8′-quinoline]-5′-carboxamide;(5S,8S)-N-(2,4-dichloro-6-methylbenzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2,4-dichlorobenzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-4-fluorobenzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8S)-N-(2-chloro-4-fluorobenzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2,4-dichloro-6-fluorobenzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-8-hydroxy-N-(2,3,4-trifluorobenzyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8S)-8-hydroxy-N-(2,3,4-trifluorobenzyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8S)-8-hydroxy-N-(2,4,6-trifluorobenzyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8S)-N-(2,4-difluorobenzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(4-fluoro-2-(trifluoromethyl)benzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8S)-N-(4-fluoro-2-(trifluoromethyl)benzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(4-chloro-2-fluorobenzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8S)-N-(4-chloro-2-fluorobenzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(4-bromo-2-fluorobenzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8S)-N-(4-bromo-2-fluorobenzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-3,4-difluorobenzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8R)-N-(2,4-dichloro-6-methylbenzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-3-(trifluoromethyl)benzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8R)-N-(2-chloro-4-fluorobenzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-N-(2-chloro-4-fluorobenzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8R)-N-(2,4-dichloro-6-fluorobenzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8R)-8-hydroxy-N-(2,3,4-trifluorobenzyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-8-hydroxy-N-(2,3,4-trifluorobenzyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8R)-N-(4-chloro-2-fluorobenzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8S)-N-(2,4-dichloro-6-methylbenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8S)-N-(2,4-dichloro-6-(hydroxymethyl)benzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8S)-N-(2,4-dichlorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-N-(2,4-dichlorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-N-(2-chloro-4-fluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-5-fluoro-8-hydroxy-N-(2,3,4-trifluorobenzyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-N-(2,4-difluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-5-fluoro-N-(4-fluoro-2-(trifluoromethyl)benzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-N-(4-chloro-2-fluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8S)-N-(2,6-dichloro-4-(trifluoromethyl)benzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-N-(2,6-dichloro-4-(trifluoromethyl)benzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8S)-N-(2,4-dichloro-6-fluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-N-(2,4-dichloro-6-fluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-N-(4-bromo-2-chlorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8S)-N-(2,3-dichlorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-N-(2,3-dichlorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-N-(2-chloro-6-methylbenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-N-(2-chloro-4,5-difluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-N-(2-chloro-4-methylbenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8R)-N-(2,4-dichloro-6-methylbenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8R)-N-(2-chloro-3-(trifluoromethyl)benzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8R)-N-(2,4-dichloro-6-(hydroxymethyl)benzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2,4-dichloro-6-(hydroxymethyl)benzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8R)-N-(2,4-dichlorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2,4-dichlorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8R)-N-(2-chloro-4-fluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-4-fluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8R)-5-fluoro-8-hydroxy-N-(2,3,4-trifluorobenzyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-5-fluoro-8-hydroxy-N-(2,3,4-trifluorobenzyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8R)-N-(2,6-dichlorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8R)-N-(2,4-difluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2,4-difluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8R)-5-fluoro-N-(4-fluoro-2-(trifluoromethyl)benzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-5-fluoro-N-(4-fluoro-2-(trifluoromethyl)benzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8R)-N-(4-chloro-2-fluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(4-chloro-2-fluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8R)-N-(2,6-dichloro-4-(trifluoromethyl)benzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2,4-dichloro-6-(difluoromethyl)benzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-4-fluoro-6-(hydroxymethyl)benzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8R)-N-(2,4-dichloro-6-fluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2,4-dichloro-6-fluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8R)-N-(4-bromo-2-chlorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(4-bromo-2-chlorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8R)-N-(2,3-dichlorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2,3-dichlorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8R)-N-(2-chloro-6-methylbenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8R)-N-(2-chloro-4,5-difluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8R)-5-fluoro-8-hydroxy-N-(2,3,6-trichlorobenzyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8R)-N-(2-chloro-4-methylbenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-4-methylbenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-3-fluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-3,6-difluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-6-fluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-4-methoxybenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-3,4-difluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-4,6-difluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-5-fluoro-N-(3-fluoro-2-(trifluoromethyl)benzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-5-fluoro-8-hydroxy-N-(2,4,6-trifluorobenzyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(4-bromo-2-fluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(4-chloro-2,3-difluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(4-chloro-2,6-difluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-4-(trifluoromethyl)benzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(3-chloro-4-fluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-5-fluoro-8-hydroxy-N-((R)-1,2,3,4-tetrahydronaphthalen-1-yl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(3-chloro-2-fluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(3-chloro-2,6-difluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-((3-chloro-5-(trifluoromethyl)pyridin-2-yl)methyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chlorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-((R)-2,3-dihydro-1H-inden-1-yl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(3,4-dichlorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-5-fluoro-8-hydroxy-N-(2-(trifluoromethyl)benzyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-5-fluoro-8-hydroxy-N-(3,4,5-trifluorobenzyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(4-cyano-2-fluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(3,4-difluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(3-chloro-5-fluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-5-fluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(3-chlorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(4-chloro-3-fluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-5-fluoro-N-(2-fluoro-4-(trifluoromethoxy)benzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2,3-difluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(4-chlorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(3,5-dichlorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-5-fluoro-8-hydroxy-N-((1S,2R)-2-phenylcyclopropyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2,6-difluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-5-fluoro-8-hydroxy-N-((S)-1,2,3,4-tetrahydronaphthalen-1-yl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-5-fluoro-8-hydroxy-N-(2-(3-(trifluoromethyl)phenoxy)ethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(3,5-difluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-5-fluoro-8-hydroxy-N-((1R,2S)-2-phenylcyclopropyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-5-fluoro-N-(2-fluorobenzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-3-methoxybenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-((S)-2,3-dihydro-1H-inden-1-yl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(3,3-dimethylbutyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-5-fluoro-8-hydroxy-N-(2-phenoxyethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(4,6-dichloro-2,3-dihydrobenzofuran-3-yl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(chroman-3-yl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-5-fluoro-8-hydroxy-N-(2-morpholino-2-phenylethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-(4,4-difluoropiperidin-1-yl)-2-(4-methylthiazol-5-yl)ethyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-((trans)-2-(2,4-dichlorophenyl)cyclopropyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2,4-dichlorobenzyl)-5-fluoro-8-hydroxy-3-methyl-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-4-fluorobenzyl)-5-fluoro-8-hydroxy-3-methyl-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-5-((2,4-dichlorobenzyl)carbamoyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline1-oxide;(5S,8S)-5-fluoro-8-hydroxy-8-methyl-N-(2,3,4-trifluorobenzyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-4-fluorobenzyl)-5-fluoro-8-hydroxy-8-methyl-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-N-(2-chloro-4-fluorobenzyl)-5-fluoro-8-hydroxy-8-methyl-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-4-fluoro-6-(hydroxymethyl)benzyl)-5-fluoro-8-hydroxy-8-methyl-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2,4-difluorobenzyl)-5-fluoro-8-hydroxy-8-methyl-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(4-chloro-2-fluorobenzyl)-5-fluoro-8-hydroxy-8-methyl-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-4,6-difluorobenzyl)-5-fluoro-8-hydroxy-8-methyl-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(4-chloro-2,3-difluorobenzyl)-5-fluoro-8-hydroxy-8-methyl-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(4-chloro-2,6-difluorobenzyl)-5-fluoro-8-hydroxy-8-methyl-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-((S)-1-(2-chloro-4-fluorophenyl)ethyl)-5-fluoro-8-hydroxy-8-methyl-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-((3,5-dichloropyridin-2-yl)methyl)-5-fluoro-8-hydroxy-8-methyl-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8)-N-((trans)-2-(2,4-dichlorophenyl)cyclopropyl)-5-fluoro-8-hydroxy-8-methyl-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-N-(2,4-dichlorobenzyl)-5-fluoro-8-hydroxy-8-(((2-hydroxyethyl)(methyl)amino)methyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8S)-N-(2,4-dichlorobenzyl)-5-fluoro-8-hydroxy-8-(((2-hydroxyethyl)(methyl)amino)methyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8S)-N-(2,4-dichlorobenzyl)-5-fluoro-8-hydroxy-8-((3-hydroxyazetidin-1-yl)methy1)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-8-(cyanomethyl)-N-(2,4-dichlorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-N-(2-chloro-4-fluorobenzyl)-8-(cyanomethyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-4-fluorobenzyl)-8-(cyanomethyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-N-(2-chloro-4-fluoro-6-(hydroxymethyl)benzyl)-8-(cyanomethyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2,4-dichlorobenzyl)-5-fluoro-8-(fluoromethyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-4-fluorobenzyl)-5-fluoro-8-(fluoromethyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(2R,5'S)-N-(2,4-dichlorobenzyl)-5′-fluoro-4-methyl-6′,7′-dihydro-5′H-spiro[morpholine-2,8′-quinoline]-5′-carboxamide;(5S,5'S)-N-(2,4-dichlorobenzyl)-5′-fluoro-2-oxo-6′,7′-dihydro-5′H-spiro[oxazolidine-5,8′-quinoline]-5′-carboxamide;(5R,5'S)-N-(2,4-dichlorobenzyl)-5′-fluoro-2-oxo-6′,7′-dihydro-5′H-spiro[oxazolidine-5,8′-quinoline]-5′-carboxamide;(2S,5′R)-N-(2,4-dichlorobenzyl)-5′-fluoro-5-oxo-6′,7′-dihydro-5′H-spiro[morpholine-2,8′-quinoline]-5′-carboxamide;(2S,5'S)-N-(2,4-dichlorobenzyl)-5′-fluoro-5-oxo-6′,7′-dihydro-5′H-spiro[morpholine-2,8′-quinoline]-5′-carboxamide;(2R,5'S)-N-(2,4-dichlorobenzyl)-5′-fluoro-5-oxo-6′,7′-dihydro-5′H-spiro[morpholine-2,8′-quinoline]-5′-carboxamide;(5S,8S)-N-(2-chloro-4-fluorobenzyl)-5-fluoro-8-hydroxy-8-((methylsulfinyl)methyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-4-fluorobenzyl)-5-fluoro-8-hydroxy-8-((methylsulfonyl)methyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2,4-dichlorobenzyl)-5-fluoro-8-hydroxy-8-(((2-hydroxyethyl)sulfonyl)methyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-4-fluorobenzyl)-5-fluoro-8-hydroxy-8-(((2-hydroxyethyl)sulfonyl)methyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8R)-N-(2,4-dichlorobenzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8S)-N-(2,4-dichlorobenzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2,4-dichlorobenzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-N-(2,4-dichlorobenzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-4-fluorobenzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-N-(2-chloro-4-fluorobenzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-N-(2,3,4-trifluorobenzyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-N-(2,3,4-trifluorobenzyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2,4-dichloro-6-fluorobenzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-N-(2,4-dichloro-6-fluorobenzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-3,4-difluorobenzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-N-(2-chloro-3,4-difluorobenzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(4-chloro-2-fluorobenzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-N-(4-chloro-2-fluorobenzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2,4-dichloro-6-(hydroxymethyl)benzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-4-fluoro-6-(hydroxymethyl)benzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2,4-difluorobenzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2,4-dichloro-3-fluorobenzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-4,6-difluorobenzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(4-chloro-2,3-difluorobenzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(3-chloro-2,4-difluorobenzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(4-chloro-2,6-difluorobenzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-((R)-1-(2,4-dichlorophenyl)ethyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-((R)-1-(2-chloro-4-fluorophenyl)ethyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-N-((R)-1-(2-chloro-4-fluorophenyl)ethyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-((3,5-dichloropyridin-2-yl)methyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-((trans)-2-(2,4-dichlorophenyl)cyclopropyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-5-fluoro-8-methoxy-N-(2,4,6-trifluorobenzyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2,4-difluorobenzyl)-5-fluoro-8-methoxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(4-chloro-2-fluorobenzyl)-5-fluoro-8-(2-hydroxyethoxy)-5,6,7,8-tetrahydroquinoline-5-carboxamide and(5S,8S)-N-(2,4-difluorobenzyl)-5-fluoro-8-(2-hydroxyethoxy)-5,6,7,8-tetrahydroquinoline-5-carboxamide.

[7] A compound represented by the following formula (L-a) or apharmaceutically acceptable salt thereof:

wherein:

R³ is independently selected from the group consisting of:

(1) hydrogen, (2) halogen, (3) C₆ alkyl and (4) —O—C₁₋₆ alkyl;

preferably R³ is (1) hydrogen;

p is 0, 1, 2 or 3;

when p is 2 or 3, each R³ is the same or different;

R¹⁶ is selected from the group consisting of:

(1) CN and (2) —CO₂R¹⁸;

R¹⁷ is selected from the group consisting of:

(1) fluoro and (2) hydroxyl; or,

R¹⁶ may form ═O with R¹⁷;

R¹⁸ is selected from the group consisting of:

(1) hydrogen and (2) C₁₋₆ alkyl.

[7-1]The compound according to [7] or a salt thereof, wherein R¹⁶ forms═O with R¹⁷.

[7-2]The compound according to [7] or a salt thereof, wherein R¹⁷ isfluoro.

[7-3]The compound according to [7-2] or a salt thereof, wherein R¹⁶ is—CN.

[7-4]The compound according to [7-2] or a salt thereof, wherein R¹⁶ is—CO₂R¹⁸.

[7-5]The compound according to [7] or a salt thereof, wherein R¹⁶ is—CO₂R; R¹⁷ is hydroxyl.

[8] A compound represented by the following formula (L-b) or apharmaceutically acceptable salt thereof:

wherein:

R³ is independently selected from the group consisting of:

(1) hydrogen, (2) halogen, (3) C₁₋₆ alkyl and (4) —O—C₁₋₆ alkyl;

preferably R³ is (1) hydrogen;

p is 0, 1, 2 or 3;

when p is 2 or 3, each R³ is the same or different;

R⁴ is selected from the group consisting of:

(1) hydrogen, (2) halogen and (3) hydroxyl.

[9] A use of a compound described in any one of [1] to [6] or apharmaceutically acceptable salt thereof or a prodrug thereof for themanufacture of a medicament for the treatment of a condition or disordermediated by P2X7 receptor antagonistic activity.

[10] The use as described in [9], wherein the condition or disorder isselected from the group consisting of: diseases of the autoimmune andinflammatory system; diseases of the nervous and neuro-immune system;diseases involved with, and without, neuroinflammation of the CentralNervous System (CNS); diseases of the cardiovascular, metabolic,gastrointestinal and urogenital systems; skeletal disorders, diseasesinvolving the secretoryfunction of exocrine glands and glaucoma,Glomerulonephritis, Chaga's Disease, chlamydia, neuroblastoma,Tuberculosis, Polycystic Kidney Disease, cancer, and acne; andcombinations thereof.

[11] A method for the treatment of a condition or disorder mediated byP2X7 receptor antagonistic activity in a mammalian subject, including ahuman, which comprises administering to a mammal in need of suchtreatment a therapeutically effective amount of a compound described inany one of [1] to [6] or a pharmaceutically acceptable salt thereof or aprodrug thereof.

[12] The method as described in [11], wherein the condition or disorderis selected from the group consisting of: diseases of the autoimmune andinflammatory system; diseases of the nervous and neuro-immune system;diseases involved with, and without, neuroinflammation of the CentralNervous System (CNS); diseases of the cardiovascular, metabolic,gastrointestinal and urogenital systems; skeletal disorders, diseasesinvolving the secretory function of exocrine glands and glaucoma,Glomerulonephritis, Chaga's Disease, chlamydia, neuroblastoma,Tuberculosis, Polycystic Kidney Disease, cancer, and acne; andcombinations thereof.

[13] A pharmaceutical composition comprising a compound or apharmaceutically acceptable salt thereof or a prodrug thereof, asdescribed in any one of [1] to [6], and a pharmaceutically acceptablecarrier.

[14] The pharmaceutical composition as described in [13], furthercomprising another pharmacologically active agent.

[15] A compound described in any one of [1] to [6] or a pharmaceuticallyacceptable salt thereof or a prodrug thereof for use in the treatment ofa condition or disorder mediated by P2X7 receptor antagonistic activity.

[16] A process for preparing a pharmaceutical composition, wherein theprocess comprises mixing a compound described in any one of [1] to [6]or a pharmaceutically acceptable salt thereof or a prodrug thereof and apharmaceutically acceptable carrier or excipient.

Examples of conditions or disorders mediated by P2X7 receptor activityinclude, but are not limited to, P2X7 related diseases.

Advantageous Effects of Invention

The tetrahydroquinoline derivatives of the present invention act asmodulators of the P2X7 receptor and have a number of therapeuticapplications, particularly in the treatment of diseases of theautoimmune and inflammatory system, diseases of the nervous andneuro-immune system, diseases involved with neuroinflammation of the CNSor diseases of the cardiovascular, metabolic, gastrointestinal andurogenital systems. More particularly, the tetrahydroquinolinederivatives of the invention are selective P2X7 receptor antagonists. Inthe discussion that follows, the invention is exemplified by referenceto the inhibition of P2X7 channel as the purinergic receptor.

The compounds of the present invention show the P2X7 receptorantagonistic activity. The compounds of the present invention may showless toxicity, good absorption, distribution, good solubility, lessprotein binding affinity other than P2X7 receptor, less drug-druginteraction, and good metabolic stability.

Especially, the present invention show excellent P2X7 antagonisticactivities as well as excellent pharmacokinetic properties. In addition,they show selectivity for the P2X7 channel as compared with other P2Xfamilies, especially P2X1 channel.

DESCRIPTION OF EMBODIMENTS

As used herein, the term “alkyl” as a group or part of a group e.g.alkoxy or hydroxyalkyl refers to a straight or branched alkyl group inall isomeric forms. The term “C₁-C₆ alkyl” refers to an alkyl group, asdefined above, containing at least 1 and at most 6 carbon atoms.Examples of such alkyl groups include methyl, ethyl, propyl, isopropyl,n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, pentan-2-yl,pentan-3-yl, 2-methylbutyl, 3-methylbutan-2-yl, isopentyl, tert-pentyl,neopentyl, n-hexyl, hexan-2-yl, hexan-3-yl, 2-methylpentyl,4-methylpentyl, 2-methylpentan-3-yl, 4-methylpentan-2-yl, 2-ethylbutyl,3-methylpentyl, 3-methylpentan-2-yl, 3-methylpentan-3-yl,2,3-dimethylbutyl, 2,3-dimethylbutan-2-yl, 3,3-dimethylbutyl,3,3-dimethylbutan-2-yl, and 2,2-dimethylbutyl.

Examples of such alkoxy groups include methoxy, ethoxy, propoxy,iso-propoxy, butoxy, iso-butoxy, sec-butoxy, tert-butoxy, n-pentoxy,pentan-2-oxy, pentan-3-oxy, 2-methylbutoxy, 3-methylbutan-2-oxy,isopentoxy, tert-pentoxy, neopentoxy, n-hexoxy, hexan-2-oxy,hexan-3-oxy, 2-methylpentoxy, 4-methylpentoxy, 2-methylpentan-3-oxy,4-methylpentan-2-oxy, 2-ethylbutoxy, 3-methylpentoxy,3-methylpentan-2-oxy, 3-methylpentan-3-oxy, 2,3-dimethylbutoxy,2,3-dimethylbutan-2-oxy, 3,3-dimethylbutoxy, 3,3-dimethylbutan-2-oxy,and 2,2-dimethylbutoxy.

The term “cycloalkyl”, as used herein, means a mono-, bicyclic- ortricyclic ring, but not limited to, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, adamantyl groups andthe like.

The term “alkenyl”, as used herein, means a hydrocarbon radical havingat least one double bond, which may be in a E- or a Z-arrangement,including, but not limited to, ethenyl, propenyl, 1-butenyl, 2-butenyland the like.

The term “halogen” refers to fluoro (—F), chloro (—Cl), bromo (—Br) andiodo (—I).

The term “haloalkyl”, as used herein, means an alkyl radical which issubstituted by halogen atom(s) as defined above including, but notlimited to, fluoromethyl, difluoromethyl, trifluoromethyl,2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl,2,2,2-trichloroethyl, 3-fluoropropyl, 4-fluorobutyl, chloromethyl,trichloromethyl, iodomethyl, bromomethyl groups and the like.

The term “heterocyclyl”, as used herein, means a saturated 3- to16-membered ring which comprises one or more heteroatoms selected fromnitrogen, oxygen and sulfur. For purposes of this invention, theheterocyclyl may be a monocyclic, bicyclic or tricyclic ring system,which may include fused, bridged or spiro ring systems. Examples of suchheterocyclyl groups include azetidinyl, 1,4-dioxanyl, pyrrolidinyl,piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl,thiomorpholinyl, tetrahy-drothienyl, 2-oxo-pyrrolidinyl,2-oxo-piperidinyl, 2-oxo-imidazolidinyl, 2-oxo-oxazolidinyl,quinuclidinyl, azabicyclo[3.2.1]octyl, 2-oxa-6-azaspiro[3.4]octyl andN-oxides thereof and S-oxides thereof.

The term “aryl”, as used herein, means unsaturated or partiallysaturated mono- or bicyclic 6-15 membered ring which consists of carbonatoms.

Examples of such aryl include, but are not limited to, phenyl, naphthyl,indanyl, indenyl, 1,2,3,4-tetrahydronaphthyl, 1,2-dihydronaphthyl,2,3-dihydro-1H-indenyl, cy-clohexenyl, cyclopentenyl,(1S,4S)-bicyclo[2.2.2]oct-2-enyl, and (1R,4S)-bicyclo[2.2.1]hept-2-enyl.Examples of —O—C₁₋₆ alkylaryl include, benzyloxy.

The term “heteroaryl” as used herein, means unsaturated and partiallysaturated mono- or bicyclic 5-15 membered ring, preferably 6-10 memberedring, which may contain 1-4 heteroatoms selected from O, N and S:Examples of such heteroaryl include, but are not limited to, thiophenyl,thiazolyl, isoxazolyl, pyrazolyl, tetrazolyl, furanyl, pyrrolyl,imidazolyl, oxazolyl, isothiazolyl, triazolyl, thiadiazolyl, pyridyl,pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, benzofuranyl,benzothiophenyl, benzotriazolyl, indolyl, indazolyl, benzoimidazolyl,pyrrolopyridyl, pyrrolopyrimidinyl, pyrazolopyridyl,pyrazolopyrimidinyl, imidazopyridinyl, furopyridyl, benzoisoxazolyl,imidazopyrazinyl, imidazopyridazinyl, imidazopyrimidinyl, quinolyl,isoquinolyl, quinazolinyl, phthalazinyl, quinoxalinyl, naphthyridinyl,pyridopyrimidinyl, and N-oxides thereof and S-oxides thereof.

R⁵ may form a saturated or unsaturated bicyclic 9 to 10 membered ringwith R⁶ which may contain a nitrogen atom, an oxygen atom or a sulfuratom; Examples of such bicyclic 9 to 10 membered ring include1,2,3,4-tetrahydronaphthalenyl, 2,3-dihydro-1H-indenyl, chromanyl,2,3-dihydrobenzofuranyl, 1,2,3,4-tetrahydroquinolinyl, indolinyl,thiochromanyl and 2,3-dihydrobenzo[b]thiophenyl.

The substituents on the ring of the compound of the present inventionmay exist on the any atoms if it is chemically allowed.

The term “protecting group”, as used herein, means a hydroxy or aminoprotecting group which is selected from typical hydroxy or aminoprotecting groups described in Protective Groups in Organic SynthesisForth Edition edited by T. W. Greene et al. (John Wiley & Sons, 2006);

The terms “treating” and “treatment”, as used herein, refer to curative,palliative and prophylactic treatment, including reversing, alleviating,inhibiting the progress of, or preventing the disorder or condition towhich such term applies, or one or more symptoms of such disorder orcondition.

As used herein, the article “a” or “an” refers to both the singular andplural form of the object to which it refers unless indicated otherwise.

In some cases, the symbol letter is written the corresponding Englishword in the present specification. For example, the symbols α, β, and δare written alpha, beta, and delta, respectively.

Included within the scope of the “compounds of the invention” are allsalts, solvates, hydrates, complexes, polymorphs, prodrugs, radiolabeledderivatives, stereoisomers and optical isomers of the compounds of thepresent invention.

The compounds of the present invention can form acid addition saltsthereof. It would be appreciated that for use in medicine, the salts ofthe compounds of the present invention should be pharmaceuticallyacceptable. Suitable pharmaceutically acceptable salts would be apparentto those skilled in the art and include those described in J. Pharm.Sci, 66, 1-19, 1977, such as acid addition salts formed with inorganicacids e.g. hydrochloric, hydrobromic, sulfuric, nitric or phosphoricacid; and organic acids e.g. succinic, maleic, formic, acetic,trifluoroacetic, propionic, fumaric, citric, tartaric, benzoic,p-toluenesulfonic, methanesulfonic or naphthalenesulfonic acid. Certainof the compounds of the present invention may form acid addition saltswith one or more equivalents of the acid. The present invention includeswithin its scope all possible stoichiometric and non-stoichiometricforms. In addition, certain compounds containing an acidic function suchas a carboxy can be isolated in the form of their inorganic salt inwhich the counter ion can be selected from sodium, potassium, lithium,calcium, magnesium and the like, as well as from organic bases.

Also within the scope of the invention are so-called “prodrugs” of thecompounds of the present invention. Thus, certain derivatives ofcompounds of the present invention which may have little or nopharmacological activity themselves, when administered into or onto thebody, can be converted into compounds of the present invention havingthe desired activity, for example, by hydrolytic cleavage. Suchderivatives are referred to as “prodrugs”. Further information on theuse of prodrugs may be found in Pro-drugs as Novel Delivery Systems,Vol. 14, ACS Symposium Series (T Higuchi and V Stella) and BioreversibleCarriers in Drug Design, Pergamon Press, 1987 (ed. E B Roche, AmericanPharmaceutical Association).

Prodrugs in accordance with the invention, for example, can be producedby replacing appropriate functionalities present in the compounds of thepresent invention with certain moieties known to those skilled in theart as ‘pro-moieties’ as described, for example, in Design of Prodrugsby H Bundgaard (Elsevier, 1985). Some examples of prodrugs in accordancewith the invention include:

(i) where the compound of the present invention contains an alcoholfunctionality (—OH), compounds wherein the hydroxy group is replacedwith a moiety convertible in vivo into the hydroxy group. Said moietyconvertible in vivo into the hydroxy group means a moiety transformablein vivo into a hydroxyl group by e.g. hydrolysis and/or by an enzyme,e.g. an esterase. Examples of said moiety include, but are not limitedto, ester and ether groups which may be hydrolyzed easily in vivo.Preferred are the moieties replaced the hydrogen of hydroxy group withacyloxyalkyl, 1-(alkoxycarbonyloxy)alkyl, phthalidyl andacyloxyalkyloxycarbonyl such as pivaloyloxymethyloxycarbonyl; and

(ii) where the compound of the present invention contains an aminogroup, an amide derivative prepared by reacting with a suitable acidhalide or a suitable acid anhydride is exemplified as a prodrug. Aparticularly preferred amide derivative as a prodrug is —NHCO(CH₂)₂OCH₃,—NHCOCH(NH₂)CH₃ or the like.

Further examples of replacement groups in accordance with the foregoingexamples and examples of other prodrug types may be found in theaforementioned references.

The compounds of the present invention, salts thereof and prodrugsthereof may be prepared in crystalline or non-crystalline form and, ifcrystalline, may optionally be hydrated or solvated. This inventionincludes within its scope stoichiometric hydrates or solvates as well ascompounds containing variable amounts of water and/or solvent.

Salts and solvates having non-pharmaceutically acceptable counter-ionsor associated solvents are within the scope of the present invention,for example, for use as intermediates in the preparation of othercompounds of the present invention and their pharmaceutically acceptablesalts.

Additionally, the compounds of the present invention may be administeredas prodrugs. As used herein, a “prodrug” of a compound of the presentinvention is a functional derivative of the compound which, uponadministration to a patient, eventually liberates the compound of thepresent invention in vivo. Administration of a compound of the presentinvention as a prodrug may enable the skilled artisan to do one or moreof the followings: (a) modify the onset of action of the compound invivo; (b) modify the duration of action of the compound in vivo; (c)modify the transportation or distribution of the compound in vivo; (d)modify the solubility of the compound in vivo; and (e) overcome a sideeffect or other difficulty encountered with the compound. Typicalfunctional derivatives used to prepare prodrugs include modifications ofthe compound that are chemically or enzymatically cleaved in vivo. Suchmodifications, which include the preparation of phosphates, amides,esters, thioesters, carbonates, and carbamates, are well known to thoseskilled in the art.

In certain of the compounds of the present invention, there may be somechiral carbon atoms. In such cases, compounds of the present inventionexist as stereoisomers. The invention extends to all optical isomerssuch as stereoisomeric forms of the compounds of the present inventionincluding enantiomers, diastereoisomers and mixtures thereof, such asracemates. The different stereoisomeric forms may be separated orresolved one from the other by conventional methods or any given isomermay be obtained by conventional stereoselective or asymmetric syntheses.

Certain of the compounds herein can exist in various tautomeric formsand it is to be understood that the invention encompasses all suchtautomeric forms.

The invention also includes isotopically-labeled compounds, which areidentical to those described herein, but for the fact that one or moreatoms are replaced by an atom having an atomic mass or mass numberdifferent from the atomic mass or mass number usually found in nature.Examples of isotopes that can be incorporated into compounds of theinvention include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorous, fluorine, iodine, and chlorine, such as ³H, 11, ¹⁴C, ¹⁸F,¹²³ and ¹²⁵I. Compounds of the invention that contain the aforementionedisotopes and/or other isotopes of other atoms are within the scope ofthe present invention. Isotopically-labeled compounds of the presentinvention, for example those into which radioactive isotopes such as ³H,¹⁴C are incorporated, are useful in drug and/or substrate tissuedistribution assays. Tritiated, i.e., ³H, and carbon-14, i.e., ¹⁴C,isotopes are particularly preferred for their ease of preparation anddetectability. ¹¹C and ¹⁸F isotopes are particularly useful in PET(positron emission tomography), and ¹²⁵ isotopes are particularly usefulin SPECT (single photon emission computerized tomography), all useful inbrain imaging. Further, substitution with heavier isotopes such asdeuterium, i.e., ²H, can afford certain therapeutic advantages resultingfrom greater metabolic stability, for example increased in vivohalf-life or reduced dosage requirements and, hence, may be preferred insome circumstances. Isotopically labeled compounds of the invention canbe generally prepared by carrying out the procedures disclosed in theSchemes and/or in the Examples/Intermediates below, then substituting areadily available isotopically labeled reagent for a non-isotopicallylabeled reagent.

The potencies and efficacies of the compounds of this invention for P2X7can be determined by calcium influx assay performed on the human clonedreceptor as described herein. Compounds of the present invention havedemonstrated antagonistic activity at the P2X7 receptor, using thefunctional assay described herein.

Compounds of the present invention and pharmaceutically acceptable saltsthereof are therefore of use in the treatment of conditions or disorderswhich are mediated via the P2X7 receptor. In particular the compounds ofthe present invention and pharmaceutically acceptable salts thereof areof use in the treatment of a wide range of diseases, syndromes, anddisorders, in particular for the treatment of diseases of the autoimmuneand inflammatory system; diseases of the nervous and neuro-immunesystem; diseases involved with, and without, neuroinflammation of theCNS; diseases of the cardiovascular, metabolic, gastrointestinal andurogenital systems; skeletal disorders, diseases involving the secretoryfunction of exocrine glands and diseases such as glaucoma,Glomerulonephritis, Chaga's Disease, chlamydia, neuroblastoma,Tuberculosis, Polycystic Kidney Disease, cancer, and acne.

Examples of diseases of the autoimmune and inflammatory system includerheumatoid arthritis, osteoarthritis, interstitial cystitis, psoriasis,septic shock, sepsis, allergic dermatitis, idiopathic pulmonaryfibrosis, allergic rhinitis, chronic obstructive pulmonary disease,airway hyper-responsiveness and asthma. Examples of asthma includeallergic asthma, mild to severe asthma, and steroid resistant asthma.

Examples of diseases of the nervous and neuro-immune system includeacute and chronic pain. Examples of acute and chronic pain includeneuropathic pain, inflammatory pain, migraine, spontaneous pain.Examples of spontaneous pain include opioid induced pain, diabeticneuropathy, postherpetic neuralgia, low back pain, chemotherapy-inducedneuropathic pain, fibromyalgia.

Examples of diseases involved with, and without, neuroinflammation ofthe CNS include cognition, sleep disorders, multiple sclerosis,epileptic seizures, Parkinson's disease, schizophrenia, Alzheimer'sdisease, Huntington's disease, Amyotrophic Lateral Sclerosis, autism,spinal cord injury and cerebral ischemia/traumatic brain injury,stress-related disorders, and mood disorders. Examples of mood disordersinclude major depression, major depressive disorder, treatment resistantdepression, bipolar disorder, seasonal affective disorder, post nataldepression, manic depression, bipolar depression, anxious depression,and anxiety. Examples of anxiety include social anxiety, post traumaticstress disorder, phobias, social phobia, special phobias, panicdisorder, obsessive compulsive disorder, acute stress disorder,separation anxiety disorder, and generalized anxiety disorder.

Examples of diseases of the cardiovascular, metabolic, gastrointestinaland urogenital systems include diabetes, diabetes mellitus, thrombosis,irritable bowel disease, irritable bowel syndrome, Crohn's disease,cardiovascular diseases (such as hypertension, myocardial infarction,ischemic heart disease, ischemia), ureteric obstruction, lower urinarytract syndrome, lower urinary tract dysfunction such as incontinence,and disease after cardiac transplantation.

Examples of a neuropathic pain include pain due to a disease, syndrome,condition, disorder, or pain state including cancer, neurologicaldisorders, spine and peripheral nerve surgery, brain tumor, traumaticbrain injury (TBI), spinal cord trauma, chronic pain syndrome,fibromyalgia, chronic fatigue syndrome, neuralgias (trigeminalneuralgia, glossopharyngeal neuralgia, postherpetic neuralgia andcausalgia), lupus, sarcoidosis, peripheral neuropathy, bilateralperipheral neuropathy, diabetic neuropathy, central pain, neuropathiesassociated with spinal cord injury, stroke, amyotrophic lateralsclerosis (ALS), Parkinson's disease, multiple sclerosis, sciaticneuritis, mandibular joint neuralgia, peripheral neuritis, polyneuritis,stump pain, phantom limb pain, bony fractures, oral neuropathic pain,Charcot's pain, complex regional pain syndrome I and II (CRPS I/II),radiculopathy, Guillain-Barre syndrome, meralgia paraesthetica,burning-mouth syndrome, optic neuritis, postfebrile neuritis, migratingneuritis, segmental neuritis, Gombault's neuritis, neuronitis,cervicobrachial neuralgia, cranial neuralgia, geniculate neuralgia,glossopharyngeal neuralgia, migrainous neuralgia, idiopathic neuralgia,intercostal neuralgia, mammary neuralgia, Morton's neuralgia,nasociliary neuralgia, occipital neuralgia, red neuralgia, Sluder'sneuralgia, sphenopalatine neuralgia, supraorbital neuralgia, vulvodynia,or vidian neuralgia.

Antagonistic activities of the compound of the present invention againstP2X7 and other P2X families can be confirmed in the suitable methodsknown to skilled in the art. For example, antagonistic activities ofcompounds of the present invention have been confirmed in Ca²⁺ influxassay and electrophysiology assay.

Activities of the compound of the present invention for each disease,syndrome, and disorder described above can be confirmed in the suitablemodel known to skilled in the art. For example, activities of compoundsof the present invention for pain are confirmed in rodent models ofpain.

It is to be understood that “treatment” as used herein includesprophylaxis as well as alleviation of established symptoms as describedabove.

A pharmaceutical composition of the invention, which may be prepared byadmixture, suitably at ambient temperature and atmospheric pressure, isusually adapted for oral, parenteral or rectal administration and, assuch, may be in the form of tablets, capsules, oral liquid preparations,powders, granules, lozenges, reconstitutable powders, injectable orinfusible solutions or suspensions or suppositories. Orally administeredcompositions are generally preferred. Tablets and capsules for oraladministration may be in unit dose form, and may contain conventionalexcipients, such as binding agents (e.g. pregelatinised maize starch,polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g.lactose, microcrystalline cellulose or calcium hydrogen phosphate);tableting lubricants (e.g. magnesium stearate, talc or silica);disintegrants (e.g. potato starch or sodium starch glycolate); andacceptable wetting agents (e.g. sodium lauryl sulphate). The tablets maybe coated according to methods well known in normal pharmaceuticalpractice.

Oral liquid preparations may be in the form of, for example, aqueous oroily suspension, solutions, emulsions, syrups or elixirs, or may be inthe form of a dry product for reconstitution with water or othersuitable vehicle before use. Such liquid preparations may containconventional additives such as suspending agents (e.g. sorbitol syrup,cellulose derivatives or hydrogenated edible fats), emulsifying agents(e.g. lecithin or acacia), non-aqueous vehicles (which may includeedible oils e.g. almond oil, oily esters, ethyl alcohol or fractionatedvegetable oils), preservatives (e.g. methyl or propyl-p-hydroxybenzoatesor sorbic acid), and, if desired, conventional flavourings or colorants,buffer salts and sweetening agents as appropriate. Preparations for oraladministration may be suitably formulated to give controlled release ofthe active compound or pharmaceutically acceptable salt thereof.

For parenteral administration, fluid unit dosage forms are preparedutilising a compound of the present invention or pharmaceuticallyacceptable salt thereof and a sterile vehicle. Formulations forinjection may be presented in unit dosage form e.g. in ampoules or inmulti-dose, utilising a compound of the present invention orpharmaceutically acceptable salt thereof and a sterile vehicle,optionally with an added preservative. The compositions may take suchforms as suspensions, solutions or emulsions in oily or aqueousvehicles, and may contain formulatory agents such as suspending,stabilising and/or dispersing agents. Alternatively, the activeingredient may be in powder form for constitution with a suitablevehicle, e.g. sterile pyrogen-free water, before use. The compound,depending on the vehicle and concentration used, can be either suspendedor dissolved in the vehicle. In preparing solutions, the compound can bedissolved for injection and filter sterilised before filling into asuitable vial or ampoule and sealing. Advantageously, adjuvants such asa local anaesthetic, preservatives and buffering agents are dissolved inthe vehicle. To enhance the stability, the composition can be frozenafter filling into the vial and the water removed under vacuum.Parenteral suspensions are prepared in substantially the same manner,except that the compound is suspended in the vehicle instead of beingdissolved, and sterilisation cannot be accomplished by filtration. Thecompound can be sterilised by exposure to ethylene oxide beforesuspension in a sterile vehicle. Advantageously, a surfactant or wettingagent is included in the composition to facilitate uniform distributionof the compound.

Lotions may be formulated with an aqueous or oily base and in generalwill also contain one or more emulsifying agents, stabilising agents,dispersing agents, suspending agents, thickening agents, or colouringagents. Drops may be formulated with an aqueous or non-aqueous base alsocomprising one or more dispersing agents, stabilising agents,solubilising agents or suspending agents. They may also contain apreservative.

The compounds of the present invention or pharmaceutically acceptablesalts thereof may also be formulated in rectal compositions such assuppositories or retention enemas, e.g. containing conventionalsuppository bases such as cocoa butter or other glycerides.

The compounds of the present invention or pharmaceutically acceptablesalts may also be formulated as depot preparations. Such long actingformulations may be administered by implantation (for examplesubcutaneously or intramuscularly) or by intramuscular injection. Thus,for example, the compounds of the present invention or pharmaceuticallyacceptable salts may be formulated with suitable polymeric orhydrophobic materials (for example as an emulsion in an acceptable oil)or ion exchange resins, or as sparingly soluble derivatives, forexample, as a sparingly soluble salt.

For intranasal administration, the compounds the present invention orpharmaceutically acceptable salts thereof may be formulated as solutionsfor administration via a suitable metered or unitary dose device oralternatively as a powder mix with a suitable carrier for administrationusing a suitable delivery device. Thus, the compounds of the presentinvention or pharmaceutically acceptable salts thereof may be formulatedfor oral, buccal, parenteral, topical (including ophthalmic and nasal),depot or rectal administration or in a form suitable for administrationby inhalation or insufflation (through either mouth or nose). Thecompounds of the present invention and pharmaceutically acceptable saltsthereof may be formulated for topical administration in the form ofointments, creams, gels, lotions, pessaries, aerosols or drops (e.g.eye, ear or nose drops). Ointments and creams may for example, beformulated with an aqueous or oily base with the addition of suitablethickening and/or gelling agents. Ointments for administration to theeye may be manufactured in a sterile manner using sterilized components.

A P2X7 antagonist may be usefully combined with anotherpharmacologically active compound, or two or more otherpharmacologically active compounds, particularly in the treatment ofinflammatory, pain and urological diseases or disorders. For example, aP2X7 antagonist, particularly a compound of the present invention, or apharmaceutically acceptable salt or solvate thereof, as defined above,may be administered simultaneously, sequentially or separately incombination with one or more agents.

Such combinations offer significant advantages, including synergisticactivity, in therapy.

The composition may contain from 0.1% to 99% by weight, preferably from10% to 60% by weight, of the active material, depending on the method ofadministration. The dose of the compound used in the treatment of theaforementioned disorders may vary in the usual way with the seriousnessof the disorders, the weight of the sufferer, and other similar factors.

A therapeutically effective amount of a compound of the presentinvention or a pharmaceutical composition thereof includes a dose rangefrom about 0.05 mg to about 3000 mg, in particular from about 1 mg toabout 1000 mg or, more particularly, from about 10 mg to about 500 mg ofactive ingredient in a regimen of about once a day or more than once aday, for example two, three or four times a day for an average (70 kg)human; although, it is apparent to one skilled in the art that thetherapeutically effective amount for active compounds of the inventionmay vary as well the diseases, syndromes, conditions, and disordersbeing treated.

For oral administration, a pharmaceutical composition is preferablyprovided in the form of tablets containing about 0.01, about 0.1, about1, about 10, about 50, about 100, about 150, about 200, about 250, andabout 500 milligrams of the inventive compound as the active ingredient.

Advantageously, a compound of the present invention may be administeredin a single daily dose, or the total daily dosage may be administered individed doses of two, three and four times daily.

Optimal dosages of a compound of the present invention to beadministered may be readily determined and may vary with the particularcompound used, the mode of administration, the strength of thepreparation, and the advancement of the disease, syndrome, condition, ordisorder. In addition, factors associated with the particular subjectbeing treated, including subject age, weight, diet and time ofadministration, will result in the need to adjust the dose to achieve anappropriate therapeutic level.

The above dosages are thus exemplary of the average case. There can beindividual instances wherein higher or lower dosage ranges are meritedof course, and such are within the scope of this invention.

Compounds of the present invention may be administered in any of theforegoing compositions and dosage regimens or by means of thosecompositions and dosage regimens established in the art whenever use ofa compound of the present invention is required for a subject in needthereof.

General Synthesis

Throughout the instant application, the following abbreviations are usedwith the following meanings:

AcOH: acetic acid

AIBN: 2,2′-azobis(isobutyronitrile)

BINAP: 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl

BzATP: 2′(3′)-O-(4-benzoylbenzoyl)adenosine-5′-triphosphateDAST N,N-diethylaminosulfur trifluorided.e.: diastereomeric excessDeoxo-Fluor™: bis(2-methoxyethyl)aminosulfur trifluorideDess-Martin periodinane:1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one

DMF: N,N-dimethylformamide

DMSO: dimethylsulfoxideDMT-MM: 4-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholiniumChloridee.e.: enantiomeric excessEtOAc: ethyl acetateEtOH: ethanolESI: electrospray ionizationEx: example(s)h: hour(s)HBTU: N,N,N′,N′-tetramethyl-O-(1H-benzotriazol-1-yl)uroniumhexafluorophosphateHPLC: high-performance liquid chromatography(M)Hz: (mega)hertzIM: intermediate(s)LHMDS: lithium hexamethyldisilazidemCPBA: m-chloroperbenzoic acidMeCN: acetonitrileMeOH: methanolmin: minute(s)MS: mass spectrometryn-BuP: tri-n-butylphosphine

NIS: N-iodosuccinimide

NMP: N-methyl-2-pyrrolidinoneNMR: nuclear magnetic resonanceNaBH₄: sodium tetrahydroborateNaH: sodium hydrideNaHMDS: sodium hexamethyldisilazide

NBS: N-bromosuccinimide NFSI:N-fluoro-N-(phenylsulfonyl)benzenesulfonamide

NMO: N-methylmorpholine oxideNH gel: amino bound silica gelPd-C: palladium on carbonRuCl(p-cymene)[(S,S)-Ts-DPEN]:[(S,S)-N-(2-amino-1,2-diphenylethyl)-p-toluenesulfonamide]chloro(p-cymene)ruthenium(II)RuCl(p-cymene)[(R,R)-Ts-DPEN]:[(R,R)-N-(2-amino-1,2-diphenylethyl)-p-toluenesulfonamide]chloro(p-cymene)ruthenium(II)SCX: super cation exchange resinTBAF tetrabutylammonium fluorideT₃P™: propylphosphonic anhydrideTBS: tert-butyldimethylsilylTBSCl: tert-butyldimethylsilyl chlorideTEMPO: 2,2,6,6-tetramethylpiperidine N-oxideTFA: trifluoroacetic acidTHF: tetrahydrofuranTLC: thin layer chromatographyTMAD: 1,1′-azobis(N,N-dimethylformamide)TMSCl: trimethylsilyl chlorideTogni reagent: 1-trifluoromethyl-3,3-dimethyl-1,2-benziodoxoletR: retention timeUV: ultravioletXantphos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

The compounds described herein are prepared using techniques known toone skilled in the art through the reaction sequences depicted inSchemes 1-18 as well as by other methods. Furthermore, in the followingschemes, where specific acids, bases, reagents, coupling agents,solvents, etc. are mentioned, it is understood that other suitableacids, bases, reagents, coupling agents, solvents, etc. may be used andare included within the scope of the present invention.

The use of “protecting groups” (PG) is well known in the art (see forexample “Protective Groups in Organic Synthesis Forth Edition edited byT. W. Greene et al. (John Wiley & Sons, 2006)”. For the purposes of thisdiscussion, it will be assumed that such protecting groups are asnecessary in place.

All starting materials in the following general syntheses may becommercially available or obtained by conventional methods known tothose skilled in the art.

All of the 5,6,7,8-tetrahydroquinoline and6,7-dihydro-5H-cyclopenta[b]pyridine derivatives of the formula I can beprepared by the procedures described in the general methods presentedbelow or by the specific methods described in the Examples section andthe Preparations section, or by routine modifications thereof. Thepresent invention also encompasses any one or more of these processesfor preparing the compounds of formula I, in addition to any novelintermediates used therein.

In the following general methods, X, R¹, R², R³, R⁴, R⁵, R⁶, R^(7a),R^(7b), R⁸, n, p, and q are as previously defined for5,6,7,8-tetrahydroquinoline and 6,7-dihydro-5H-cyclopenta[b]pyridinederivatives of the formula I unless otherwise stated.

Syntheses detailing the preparation of the compounds of formula I in asequential manner are presented in the following reaction schemes. Thephrase “amidation” is used here, and it means coupling a carboxylic acidwith an amine using a coupling agent such as HBTU, DMT-MM, and T₃P™ inan inert solvent such as DMF and dichloromethane in the presence of abase such as trialkylamine at temperature of 0 to 50° C.

The following illustrates a preparation of the desired compounds offormula I (Scheme 1). X is N (II and I-a), X is N-oxide (I-b), PG is acarboxyl-protecting group, R¹, R², R³, R⁴, R⁵, R⁶, R^(7a), R^(7b), R⁸,n, p, and q are as defined above.

The compounds of formula I-a can be prepared by deprotection ofcarboxyl-protecting group of the compounds formula II and then amidationbetween the compounds of formula III. Typical PG includes, but notlimited to: methyl, ethyl, t-butyl. The typical deprotection methods ofPG are described in above reference [Protective Groups in OrganicSynthesis Forth Edition]. The following amidation method is described inabove. Compounds of formula II can be prepared as described in theexperimental part below. The compounds of formula I-b can be prepared byoxidation of the compounds of formula I-a with an oxidizing reagent suchas mCPBA in a solvent such as halogenated hydrocarbons at temperature of−10 to 40° C.

The compounds of formula II use for the synthesis of compounds of thepresent invention are prepared as described in Schemes 2, 3, and 4. R³,R⁴, p, n, and PG are as defined above. The compounds of formula II canbe prepared from the compounds of formula IV by the following steps;alkenylalkylation (Step 1), intramolecular Heck reaction (Step 2),alcoholysis (Step 3), nucleophilic addition (Step 4), oxidative cleavage(Step 5), and reduction (Step 6).

The compounds of formula V can be prepared by alkylation of thecompounds of formula IV with an alkylation reagent such asalkenylalkylhalides in the presence of the base such as NaHMDS in thesuitable solvent such as THF at temperature of −100 to −60° C. (Step 1).The compounds of formula VI can be prepared from the compounds offormula V by intramolecular Heck reaction which is carried out with apalladium catalyst and a base such as Pd(Ac)₂ and triethylamine in thepresence of a phosphine ligand such as BINAP, Xantphos in a suitablesolvent such as MeCN at temperature of 50- to 150° C. (Step 2). Thecompounds of formula II-e-1 can be prepared by alcoholysis of thecompounds of formula VI with an acids such as TMSCl, HCl in the suitable(aqueous) alcohols such as MeOH at temperature of 50- to 100° C. (Step3). The compounds of formula II-e-2 can be prepared by nucleophilicaddition the compounds of formula II-e-1 with an electrophile such asNFSI or Togni reagent in the presence of a base such as NaHMDS in asuitable solvent such as THF at temperature of −100 to −60° C. (Step 4).The compounds of formula II-c can be prepared by oxidative cleavagereaction of the compounds of formula II-e-2 with an oxidizing reagentsuch as ozone and following treatment with a reducing agent such asdimethylsulfide or triphenylphosphine in a suitable solvent such asalcohol and/or halogenated hydrocarbons at temperature of −80 to −40° C.(Step 5). The compounds formula II-d can be prepared by reduction of thecompounds formula II-c with a reducing reagent such as NaBH₄ in asuitable solvent such as MeOH, THF at temperature of −10 to 70° C. Thealternative method for the preparation of the compounds of formula II-dfrom II-c by transfer hydrogenation with a hydrogen donor such as formicacid in the presence of metal catalyst such as RuCl(p-cymene)[Ts-DPEN]and a base such as triethylamine in a suitable solvent such as DMF attemperature of −10 to 70° C. (Step 6). The diastereo isomers can beseparate by silica gel column chromatography or preparative TLC. In theScheme 2, the reaction of Step 4 can be skipped to afford the compoundsof formulae II-c and II-d, which are hydrogen as R⁴.

The following illustrates a preparation of the desired compounds offormula II-v (Scheme 3). The compounds of formula II-v can be preparedfrom the compounds of formula II-c by the following steps;Horner-Wadsworth-Emmons (HWE) reaction (Step 1), and hydrogenation (Step2).

The HWE reaction is carried out for preparation of the compounds offormula VII, the compounds of formula II-c treated with a trialkylphosphono acetate such as t-butyl dimethylphosphonoacetate in thepresence of a base in a suitable solvent such as THF at temperature of−40 to 50° C. (Step 1). The compounds of formula II-v can be prepared byhydrogenation of the compounds of formula VII with a hydrogen in thepresence of a metal catalyst such as platinum oxide, palladium in asuitable solvent such as alcohols at temperature of 0 to 40° C.

The following illustrates a preparation of the desired compounds offormulae II-s and II-y (Scheme 4).

The compounds of formula II-s can be prepared by alkylation of thecompounds of formula II-d with an alkylation reagent such asalkylhalides, alkenylalkylhalides in the presence of a base, and/oradditives such as silver(I)oxide in a suitable solvent such as THF, NMPat temperature of −10 to 100° C. (Step 1a). The compounds of formulaII-y can be prepared by deoxygenative fluorination of the compounds offormula II-d with a deoxygenative fluorination reagent such as DAST,Deoxo-Fluor™ in a suitable solvent such as halogenated hydrocarbons,ethers at temperature of −50 to 20° C. (Step 1b).

Compounds of formula III, if not commercially available, can be preparedby known procedures or following procedures outlined in Scheme 5. R⁵ andR⁶ are hydrogen, q is 0, R⁸ is aryl. The compounds formula III-a can beprepared from the compounds of formula VIII by the following steps;bromination (Step 1), fluorination (Step 2), and reduction (Step 3). Thecompounds of formula III-b can be prepared from the compounds of formulaVIII by the following steps; bromination (Step 1), nucleophilicsubstitution (Step 4), and reduction (Step 3).

The bromination is carried out for the compounds of formula VIII with abromine source such as NBS in the presence of a radical initiator suchas AIBN in a suitable solvent such as carbon tetrachloride attemperature of 50- to 100° C. to afford the compounds of formulae IX andX (Step 1). The fluorination to the compounds of formula IX is carriedout with a fluorine source such as silver tetrafluoroborate to affordthe compounds of formula XI (Step 2). The compounds of formula XII canbe prepared by nucleophilic substitution of the compounds of formula Xwith a suitable nucleophile such as sodium acetate in a suitable solventsuch as AcOH at temperature of 80- to 120° C. The compounds of formulaeIII-a and III-b can be prepared by reduction of the compounds offormulae XI and XII with a suitable reducing reagent such as borane-THFcomplex in a suitable solvent such as THF at temperature of −10 to 80°C.

The following illustrates a preparation of the desired compounds offormulae I-c and I-d (Scheme 6). R¹ and R² form ketone (I-c) and R¹ ishydrogen, R² is hydroxyl (I-d), R³, R⁴, R⁵, R⁶, R^(7a), R^(7b), R⁸, n,p, and q are as defined above.

The compounds of formula I-d can be prepared by the same procedure asdescribed in the Step 6 in Scheme 2. The diastereoisomers of thecompounds of formula I-d can be separate by silica gel columnchromatography or preparative TLC. The compounds of formula I-c can beprepared by oxidation of the compounds of formula I-d with an oxidizingreagent such as Dess-Martin periodinane, TEMPO, andN-t-butylphenylsulfinimidoyl chloride in a suitable solvent such asdichloromethane, toluene at temperature of −10 to 70° C.

The following illustrates a preparation of the desired compounds offormulae I-c, and I-f (Scheme 7). R¹ and R² form methylene (I-e), R¹ andR² form ketone (I-c) and R 1 is hydroxyl, R² is hydroxymethyl (I-f), R³,R⁴, R⁵, R⁶, R^(7a), R^(7b), R⁸, n, p, and q are as defined above.

The compounds of formula I-c can be prepared by the same procedure asdescribed in the Step 5 in Scheme 2. The compounds of formula I-f can beprepared by dihydroxylation of the compounds of formula I-e with anoxidizing reagent such as osmium tetroxide in the presence or absence ofco-oxidants such as NMO in a suitable solvent such as alcohols and waterat temperature of −10 to 60° C.

The following illustrates a preparation of the desired compounds offormulae I-g, and I-h (Scheme 8). R¹ and R² form ketone (I-c), R¹ and R²form methylene (I-e), R¹ and R² form epoxide (I-g), and R¹ is hydroxyl,R² is nucleophilic group (Nu) such as acyloxy groups, hydroxides,alkoxides, fluoride, cyano, amines, azides, sulfides (I-h), R³, R⁴, R⁵,R⁶, R^(7a), R^(7b), R⁸, n, p, and q are as defined above.

The compounds of formula I-g can be prepared by epoxidation of thecompounds of formula I-e with NBS in a suitable solvent such as aqueoustert-butanol at temperature of 30- to 80° C. and then treatment with abase such as NaOH at temperature of −10 to 10° C. The compounds offormula I-g can be prepared by epoxidation of the compounds of formulaI-c with a sulfur ylide reagent such as dimethyloxosulfonium methylidein a suitable solvent such as DMSO at temperature of −10 to 50° C. Thediastereo isomers can be separate by silica gel column chromatography orpreparative TLC. The nucleophilic addition of the compounds of formulaI-g for the synthesis of the compounds of formula I-h is carried outwith the nucleophiles such as alkali metal hydroxide, alkali metalalkoxide, acyloxy groups, alkali metal cyanide, alkali metal fluoride,substituted or unsubstituted alkylsulfide, and amine or thecorresponding ammonium salt of nucleophiles in a suitable solvent suchas halogenated hydrocarbons, ethers, aromatic hydrocarbons, amides,inert amines, sulfoxides at temperature of −80 to 100° C. in thepresence or in the absence of a catalyst such as copper salts or zincsalts.

The following illustrates a preparation of the desired compounds offormulae I-i, I-j, and I-k (Scheme 9). LvG and LvG¹ are leaving groupssuch as halogen, hydroxyl, sulfonate, azide, imidazole. In the casewhere R^(10a) is LvG substituted C₁-C₂alkyl and Y¹ and Y² are hydrogen(I-h-1 and I-j) or R^(10a) is hydrogen and Y¹ and Y² form carbonyl(I-h-1, I-i, and I-k), R³, R⁴, R⁵, R⁶, R^(7a), R^(7b), R⁸, R^(9a), n, p,and q are as defined above.

The compounds of formula I-i can be prepared by amidation of thecompounds of formula I-h-1 (R^(10a) is hydrogen) with a carboxylic acidXIII (LvG is hydroxyl) under “amidation” condition as described above,or with a activated carboxylic acid XIII such as acid halide (LvG ishalogen) in a suitable base such as trialkylamine in a suitable solventsuch as dichloromethane at temperature of −30 to 20° C. In the casewhere n is 0, the cyclized compounds of formula I-k can be prepared inthis step without following “cyclization” step. In the case where LvG¹is not hydroxyl, the compounds of formulae I-j and I-k can be preparedby cyclization of the compounds of formula I-i or I-h-1 (R^(10a) is LvG¹substituted C₁-C₂alkyl) in the presence of a suitable base such aspotassium tert-butoxide in a suitable solvent such as alcohol and/orhalogenated hydrocarbons at temperature of −20 to 50° C. In the casewhere LvG¹ is hydroxyl, the compounds of formulae I-j and I-k can beprepared by intramolecular Mitsunobu reaction of the compounds offormula I-h-1 or I-i with a Mitsunobu reagents such asN,N,N′,N′-tetraalkylazodicarboxamide or dialkylazodicarboxylate in thepresence of trialkylphosphine or triarylphosphine in a suitable solventsuch as THF at temperature of −40 to 80° C.

The following illustrates a preparation of the desired compounds offormula I-1 (Scheme 10). R¹ is hydroxyl, R² is C₁alkylthio-R^(9a), m is0 (I-h-2), or m is 1 or 2 (I-1), R³, R⁴, R⁵, R⁶, R⁷, R^(7b), R⁸, R^(9a),n, p, and q are as defined above.

The compounds of formula I-1 can be prepared by oxidation of thecompounds formula I-h-2 with an oxidizing reagent such as mCPBA in asuitable solvent such as halogenated hydrocarbons at temperature of −20to 50° C.

The following illustrates a preparation of the desired compounds offormulae I-m and I-n (Scheme 11). R¹ is hydroxyl, R² is C₁alkylazide(I-h-3), or R¹ and R² form aziridine (I-m), or R¹ is amino, R² ishydroxyC₁alkyl (I-n), R³, R⁴, R⁵, R⁶, R^(7a), R^(7b), R⁸, R^(9a), n, p,q, and PG are as defined above.

The compounds of formula I-m can be prepared by aziridine formation ofthe compounds formula I-h-3 with a triphenylposphine in a suitablesolvent such as aqueous MeCN at temperature of 20- to 100° C. (Step 1).The compounds of formula I-n can be prepared by following reactions,protection of aziridine (Step 2), nucleophilic ring opening andhydrolysis (Step 3), and deprotection (Step 4). The suitable PG such as2-nitrophenylsulfonyl group, the protection and deprotection reactionscan be performed in the usual manner. The compounds of formula XV can beprepared by nucleophilic addition and then hydrolysis of the compoundsof formula XIV with a metal carboxide such as alkali metal acetoxide ina suitable solvent such as DMF at temperature of 60- to 120° C. andfollowed by hydolysis with an alkali metal hydroxide such as NaOH in asuitable solvent such as DMF at room temperature. The compounds offormula I-n can be prepared by deprotection of the compounds of formulaXV by the usual manner such as 4-mercaptobenzoic acid in a suitablesolvent such as DMF at temperature of 70- to 120° C.

The following illustrates a preparation of the desired compounds offormula I-o (Scheme 12). R¹ is amino, R² is hydroxyC₁alkyl (I-n), R³,R⁴, R⁵, R⁶, R^(7a), R^(7b), R⁸, R^(9a), LvG, LvG¹, n, p, and q are asdefined above.

The compounds of formula I-o can be prepared by the same procedure asdescribed in Scheme 9 from the compounds of formula I-n via thecompounds of formula XVI.

The following illustrates a preparation of the desired compounds offormulae I-p, I-q, and I-r (Scheme 13). R¹ is hydrogen and R² ishydroxyl (I-d), R is methyl or phenyl, R² is thioester (I-p), R² issulfide (I-q), R² is sulfoxide or sulfone (I-r), R³, R⁴, R⁵, R⁶, R^(7a),R^(7b), R⁸, R^(9a), m, n, p, and q are as defined above.

The compounds of formula I-p can be prepared by Mitsunobu reaction ofthe compounds of formula I-d with a thiocarboxylic acid such asthioacetic acid, thiobenzoic acid under Mitsunobu reaction condition asdescribed above.

The compounds of formula I-q can be prepared by S-alkylation of thecompounds of formula I-p with an alkylation reagent such as dimethylsulfonate, alkylhalides in the presence of alkali metal hydroxide in asuitable solvent such as halogenated hydrocarbons, ethers, alcohols attemperature of −20 to 50° C. The compounds of formula I-r can beprepared by the same procedures as described in Scheme 10.

The following illustrates a preparation of the desired compounds offormulae I-s, I-t and I-u (Scheme 14). R¹ is hydrogen and R² isalkenylalkoxide (I-s), R² is hydroxyalkoxide (I-t), R² is hydroxysubstituted hydroxyalkoxide (I-u), R⁴, R⁵, R⁶, R^(7a), R^(7b), and R⁸are as defined above.

The compounds of formula I-t can be prepared by oxidation of thecompounds of formula I-s with an oxidizing reagent such as ozone attemperature of −100 to −60° C. and then treated with sodiumtetrahydroborate in a suitable solvent such as halogenated hydrocarbonsand/or alcohols. The compounds of formula I-u can be prepared by thesame procedure of the “dihydroxylation” in Scheme 7.

The following illustrates a preparation of the desired compounds offormulae I-w, and I-x (Scheme 15). R¹ is hydrogen and R² is “Protectedcarboxylic acid” alkyl (I-v), R² is carboxylic acid alkyl (I-w), R² isaminocarboxylalkyl (I-x), R⁴, R⁵, R⁶, R^(7a), R^(7b), R⁸, R^(9d) andR^(10d) are as defined above.

The compounds of formula I-w can be prepared by deprotection of the PGfrom the compounds of formula I-v. The compounds of formula I-x can beprepared by “amidation” of the compounds of formula I-w with a couplingagent and amines. The general condition of “amidation” is described inabove.

The following illustrates a preparation of the desired compounds offormula II-e-2 (Scheme 16). R⁴ is hydroxyl or fluoro, R³, p, n, and PGare as defined above. The compounds of formula II-e-2 also can beprepared from the compounds of formula XVII by the following steps;alkenylacylation (Step 1), intramolecular Heck reaction (Step 2),cyanohydrination and deoxygenative fluorination (Step 3), andalcoholysis (Step 4).

The compounds of formula XVIII can be prepared by alkenylacylation ofthe compounds of formula XVII, which is carried out by the followingprocedure. The preparation of the Grignard reagents of the compounds offormula XVII is carried out by the treatment of the compounds of formulaXVII with a Turbo Grignard reagent such as 2-propylmagnesium chloridelithium chloride complex in the suitable solvent such as THF attemperature of −20 to 10° C. The compounds of formula XVIII can beprepared by the following addition of an alkenylalkylacylhalides in thesuitable solvent such as THF at temperature of −50 to 0° C. (Step 1).The compounds of formula XIX can be prepared from the compounds offormula XVIII by the same procedure as described in Scheme 2 Step 2(Step 2). The compounds of formula XX can be prepared bycyanohydrination and following deoxygenative fluorination of thecompounds of formula XIX. The cyanohydrination of the compounds offormula XIX is carried out with the cyanide source such astrimethylsilyl cyanide in the presence of a catalyst such as NMO in asuitable solvent such as THF at temperature of −10 to 30° C. And thendeoxygenative fluorination is carried out by the same procedure asdescribed in Scheme 4 Step 1b (Step 3). The compounds of formula II-e-2can be prepared from the compounds of formula XX by the same procedureas described in Scheme 2 Step 3 (Step 4).

The following illustrates a preparation of the desired compounds offormula II-e-2 (Scheme 17). R³, R⁴, p, n, and PG are as defined above.The compounds of formula II-e-2 (R⁴ is fluoro) also can be prepared fromthe compounds of formula XVII by the following steps; alkenylalkylation(Step 1), intramolecular Heck reaction (Step 2), and deoxygenativefluorination (Step 3).

The compounds of formula XXII, II-e-2 (R⁴ is hydroxyl), and II-e-2 (R⁴is fluoro) can be prepared by the same procedure as described in Scheme16 Step 1 with an alkylation reagent of XXI (Step 1), Scheme 2 Step 2(Step 2), and Scheme 4 Step 1b (Step 3).

The following illustrates a preparation of the desired compounds offormula I-g (Scheme 18). R³, R⁴, R⁵, R⁶, R^(7a), R^(7b), R⁸, p, n, q,and PG are as defined above. The compounds of formula I-g also can beprepared from the compounds of formula II-e-2 by the following steps;hydrolysis (Step 1), iodolactonization (Step 2), and nucleophilicamidation (Step 3).

The compounds of formula XXIII can be prepared from the compounds offormula II-e-2 by hydrolysis with a base such as NaOH in a suitablesolvent such as MeOH, THF at temperature 0 to 40° C. The compounds offormula XXIII also can be prepared by hydrolysis with an enzyme such aslipase in a suitable solvent such as phosphate buffer at temperature 20to 40° C. (Step 1). The compounds of formula XXIV can be prepared fromthe compounds of formula XXIII by iodolactonization which is carried outin the presence of iodine or NIS and a base such as K₂CO₃ in a suitablesolvent such as MeCN, DMF, DMSO at temperature 0 to 40° C. (Step 2). TheStep 1 and Step 2 can be carried out in one-pot. The compounds offormula I-g can be prepared by nucleophilic amidation of the compoundsof formula XXIV with an amine III in the presence of a base such asK₂CO₃ in a suitable solvent such as DMF, DMSO, MeCN at temperature of 0to 40° C. (Step 3).

The following illustrates a preparation of the desired compounds offormula II-e-2 (Scheme 19). R⁴ is fluoro, R³, p, n, and PG are asdefined above. The compounds of formula II-e-2 (R⁴ is fluoro) also canbe prepared from the compounds of formula V by the following steps;reduction (Step 1), organocatalytic fluorination (Step 2), oxidation(Step 3), protection (Step 4), and intramolecular Heck reaction (Step5).

The compounds of formula XXV can be prepared by reduction of thecompounds of formula V with a reducing reagent such asDiisobutylaluminium hydride in a suitable solvent such as toluene, THFat temperature of −78 to 0° C. (Step 1). The compounds of formula XXVIcan be prepared by organocatalytic fluorination of the compounds offormula XXV, which is carried out with an organocatalyst andfluorination reagent such as proline, imidazolidinone organocatalystsand NFSI, Selectfluor (registered trademark) in a suitable solvent suchas DMF, THF, toluene, and ether at temperature −20 to 50° C. (Step 2).The compounds of formula XXVII can be prepared by oxidation of thecompounds of formula XXVI with an oxidizing reagent such as sodiumchlorite in a suitable solvent such as tert-BuOH at temperature of −10to 40° C. (Step 3). The compound of formula XXVIII can be prepared byprotection of the compound of formula XXVII (Step 4). The compound offormula II-e-2 (R⁴ is fluoro) can be prepared from the compounds offormula XXVIII by cyclization with a palladium catalyst and a base suchas Pd(OAc)₂ and N,N-Diisopropylethylamine in the presense of a phosphineligand such as BINAP, Xantphos in a suitable soluvent such as DMF attemperature of 50 to 150° C. as described in the Step 5. The compound offormula II-e-2 (R⁴ is fluoro) can be also prepared from the compounds offormula V by the same procedure as described in the Step 2, Step 3, andStep 4 in Scheme 2.

The invention is illustrated in the following non-limiting examples inwhich, unless stated otherwise: all reagents are commercially available,all operations were carried out at room or ambient temperature, that is,in the range of about 18-25° C.; evaporation of solvent was carried outusing a rotary evaporator under reduced pressure with a bath temperatureof up to about 60° C.; reactions were monitored by thin layerchromatography (TLC) and reaction times are given for illustration only;the structure and purity of all isolated compounds were assured by atleast one of the following techniques: TLC (Merck silica gel 60 F₂₅4precoated TLC plates or Merck NH₂ F₂₅₄₈ precoated HPTLC plates), massspectrometry or nuclear magnetic resonance (NMR). Yields are given forillustrative purposes only. Flash column chromatography was carried outusing Merck silica gel 60 (230-400 mesh ASTM) or Fuji SilysiaChromatorex™ DU3050 (Amino Type, 30-50 microm) or Biotage silica (32-63mm, KP-Sil) or Biotage amino bounded silica (35-75 mm, KP-NH). SCXcartridge column chromatography was carried out using Biotage ISOLUTE™SCX-2 (1 g, 6 mL) SPE column. The purification of compounds using HPLCwas performed by the following apparatus and conditions; Apparatus;Waters MS-trigger AutoPurification™ system Column; Waters XTerra C18,19×50 mm, 5 mm particle, solvent systems; Methanol or acetonitrile/0.05%(v/v) formic acid aqueous solution, or; methanol or acetonitrile/0.01%(v/v) ammonia aqueous solution. Low-resolution mass spectral data (ESI)were obtained by the following apparatus and conditions: Apparatus;Waters Alliance HPLC system on ZQ or ZMD mass spectrometer and UVdetector. NMR data was determined at 270 MHz (JEOL JNM-LA 270spectrometer), 300 MHz (JEOL JNM-LA300), 400 MHz (JEOL ECZ 400S) usingdeuterated chloroform (99.8% D) or dimethylsulfoxide (99.9% D) assolvent unless indicated otherwise, relative to tetramethylsilane (TMS)as internal standard in parts per million (ppm); conventionalabbreviations used are: s=singlet, d=doublet, t=triplet, q=quartet,quin=quintet, m=multiplet, br=broad, etc. Chemical symbols have theirusual meanings; microL (microliter(s)), microg (microgram(s)), M (mol(s)per liter), L (liter(s)), mL (milliliter(s)), g (gram(s)), mg(milligram(s)), mol (moles), mmol (millimoles).

Conditions for determining HPLC retention time:

Method A:

Apparatus: Waters ACQUITY UPLC/ACQUITY PDA Detector/ZQ 2000

Column: Waters ACQUITY BEH C18, 2.1×100 mm

Column temperature: 60° C.

PDA detection (scan range): 200-400 nm

MS detection: ESI positive/negative mode

Solvents:

A1: 10 mM ammonium acetate aqueous solution

B1: acetonitrile

Time(min) A1(%) B1(%) 0 95 5 0.1 95 5 1.8 5 95 2.3 95 5 Run time 3 minFlow rate 0.7 mL/min

Method B:

Apparatus: Waters ACQUITY UPLC/ACQUITY PDA Detector/ZQ 2000

Column: YMC Meteoric core C18, 2.1×100 mm

Column temperature: 60° C.

PDA detection (scan range): 200-400 nm

MS detection: ESI positive/negative mode

Solvents:

A1: 10 mM ammonium acetate aqueous solution

B1: acetonitrile

Time(min) A1(%) B1 (%) 0 95 5 0.1 96 5 1.8 5 95 2.3 5 95 2.31 95 5 Runtime 3 min Flow rate 0.7 mL/min

Method C:

Apparatus: Waters ACQUITY UPLC/ACQUITY PDA Detector/ZQ 2000

Column: Waters ACQUITY BEH C18, 2.1×100 mm

Column temperature: 60° C.

PDA detection (scan range): 200-400 nm

MS detection: ESI positive/negative mode

Solvents:

A1: 10 mM ammonium acetate aqueous solution

B1: acetonitrile

Time(min) A1(%) B1(%) 0 95 5 0.1 95 5 1.8 5 95 2.3 5 95 2.31 95 5 Runtime 3 min Flow rate 0.7 mL/min

Method D:

Apparatus: Waters ACQUITY UPLC/ACQUITY PDA Detector/ZQ 2000

Column: YMC Triart C18, 2.1×100 mm, 1.9 microm particle

Column temperature: 60° C.

PDA detection (scan range): 200-400 nm MS detection: ESIpositive/negative mode

Solvents:

A1: 10 mM ammonium acetate aqueous solution

B1: acetonitrile

Time(min) A1(%) B1(%) 0 90 10 0.05 90 10 1.9 5 95 2.5 5 95 2.51 90 10Run time 3 min Flow rate 0.75 mL/min

Method E

Apparatus: Waters Alliance 2695/2996 PDA

Column: DAICEL CHIRALCEL OJ-H, 4.6 mm×250 mm

Column temperature: 40° C.

UV detection: 270 nm

Solvents: n-hexane/2-propanol/diethylamine=95/5/0.1

Flow rate: 1 mL/min

Run time: 40 min

Method F

Apparatus: Waters Alliance 2695/2996 PDA

Column: DAICEL CHIRALPAK IC-3, 4.6 mm×250 mm

Column temperature: 40° C.

UV detection: 265 nm

Solvents:

A2: 0.1% diethylamine in n-hexane

B2: 0.1% diethylamine in 2-propanol

Time(min) A2(%) B2(%) 0 85 15 15 85 15 30 50 50 40 50 50 40.01 85 15 Runtime 60 min Flow rate 1 mL/min

Method G

Apparatus: Waters Alliance 2695/2996 PDA

Column: DAICEL CHIRALPAK AD-H 4.6 mm×250 mm

Column temperature: 40° C.

UV detection: 265 nm

Solvents: n-hexane/ethanol/diethylamine=94/6/0.1

Flow rate: 1 mL/min

Run time: 30 min

Method H

Apparatus: Waters Alliance 2695/2996 PDA

Column: DAICEL CHIRALCEL OD-H, 4.6 mm×250 mm

Column temperature: 40° C.

UV detection: 270 nm

Solvents: n-hexane/2-propanol/diethylamine=95/5/0.1

Flow rate: 1 mL/min

Run time: 20 min

Method I

Apparatus: Waters Alliance 2695/2996 PDA

Column: DAICEL CHIRALPAK AD-H, 4.6×250 mm

Column temperature: 40° C.

UV Detection: 265 nm

Solvents: n-hexane/ethanol/diethylamine=88/12/0.1

Flow rate: 1 mL/min

Run time: 30 min

Method J

Apparatus: Waters Alliance 2695/2996 PDA

Column: DAICEL CHIRALCEL OD-H, 4.6 mm×250 mm

Column temperature: 40° C.

UV detection: 265 nm

Solvents: n-hexane/2-propanol/diethylamine=85/15/0.1

Flow rate: 1 mL/min

Run time: 50 min

Method K

Apparatus: Waters Alliance 2695/2996 PDA

Column: DAICEL CHIRALCEL OJ-H, 4.6 mm×250 mm

Column temperature: 40° C.

UV detection: 265 nm

Solvents: n-hexane/ethanol/diethylamine=90/10/0.1

Flow rate: 1 mL/min

Run time: 45 min

Method L

Apparatus: Waters Alliance 2695/2996 PDA

Column: Daicel CHIRALPAK IC

Column Temperature: 40° C.

UV detection: 245 nm

Solvents: n-hexane/2-propanol=90/10

Flow rate: 1 mL/min

Run time: 35 min

Preparation of Intermediates II

General Procedure: Scheme 2, Step 1

To a solution of substrate (1.0 eq.) in THF was added dropwise 1.1 MNaHMDS in THF solution (1.2 eq.) at −78° C. under N₂ atmosphere. Afteraddition, the mixture was stirred at −78° C. for 2 h. A THF solution ofalkenylalkylhalide was added dropwise to the mixture at −78° C. and themixture was stirred at this temperature for 1 h. The mixture was warmedto room temperature. After being stirred at room temperature untilcomplete reaction, the mixture was quenched with water. The mixture wasextracted with EtOAc twice and washed successively with 10% aq. citricacid, aq. NaHCO₃, and brine. The extracts were combined, dried overNa₂SO₄, and concentrated in vacuo. The resulting residue was purified bysilica gel column chromatography to afford the following intermediates(Table 1).

TABLE 1 Intermediates Structure Chemical Name Substratealkenylalkylhalide V-1

2-(2-chloropyridin-3-yl) hex-5-enenitrile

V-2

2-(2-chloropyridin-3-yl) pent-4-enenitrile

V-3

2-(2-chloro-5-fluoro- pyridin-3-yl)hex-5-enenitrile

V-4

2-(2-chloro-5-methyl- pyridin-3-yl)hex-5-enenitrile

IM V-1

¹H NMR (CDCl₃) delta 8.40 (1H, dd, J=4.9, 1.8 Hz), 7.92 (1H, dd, J=7.3,1.8 Hz), 7.34 (1H, dd, J=7.3, 4.9 Hz), 5.80 (1 H, ddt, J=17.1, 10.4, 7.3Hz), 5.16 (1H, br d, J=17.1 Hz), 5.11 (1H, br d, J=10.4 Hz), 4.27 (1H,dd, J=9.2, 4.9 Hz), 2.42-2.27 (2H, m), 2.04-1.90 (2H, m).

MS (ESI) m/z: 207.1 (M+H)⁺.

IM V-2

¹H NMR (CDCl₃) delta 8.40 (1H, dd, J=4.9, 1.8 Hz), 7.89 (1H, dd, J=7.9,1.8 Hz), 7.34 (1H, dd, J=7.9, 4.9 Hz), 5.83 (1 H, ddt, J=17.1, 9.8, 7.3Hz), 5.24 (1 H, br d, J=9.8 Hz), 5.21 (1H, br d, J=17.1 Hz), 4.35 (1H,dd, J=7.9, 4.9 Hz), 2.73 (1H, m), 2.61 (1H, m).

MS (ESI) m/z: 193.2 (M+H)⁺.

IM V-3

¹H NMR (CDCl₃) delta 8.28 (1H, dd, J=15.3, 3.1 Hz), 7.69 (1H, dd, J=7.9,3.1 Hz), 5.79 (1 H, ddt, J=17.1, 10.4, 6.1 Hz), 5.18 (1 H, br dd,J=17.1, 1.2 Hz), 5.12 (1 H, br dd, J=10.4, 1.2 Hz), 4.24 (1H, dd, J=9.8,5.5 Hz), 2.44-2.28 (2H, m), 2.08-1.92 (2H, m).

MS (ESI) m/z: 225.0 (M+H)⁺.

IM V-4

¹H NMR(CDCl₃)delta 8.19 (1H, d, J=1.8 Hz), 7.71 (1H, d, J=1.8 Hz), 5.80(1H, ddt, J=17.1, 10.4, 6.1 Hz), 5.16 (1H, br d, J=17.1 Hz), 5.10 (1H,br d, J=10.4 Hz), 4.23 (1H, m), 2.41-2.25 (2H, m), 2.37 (3 H, s),2.06-1.90 (2H, m).

MS (ESI) m/z: 221.2 (M+H)⁺.

General Procedure: Scheme 2, Step 2

A mixture of substrate (1.0 eq.), triethylamine (3.0 eq.), (+/−)-BINAP(0.135 eq.), and Pd(OAc)₂ (0.135 eq.) in MeCN was heated at reflux untilcomplete reaction. After cooling at room temperature, NH gel was addedto the mixture and the mixture was filtered. The filter cake was washedwith EtOAc. The filtrate was concentrated in vacuo. EtOAc was added tothe resulting residue and the insoluble material was removed byfiltration. Water was added to the filtrate, the mixture was extractedwith EtOAc twice. The extracts were washed with brine, dried overNa₂SO₄, and concentrated in vacuo. The resulting residue was purified bysilica gel column chromatography to afford the following intermediates(Table 2).

TABLE 2 Intermediates Structure Chemical Name Substrate VI-1

8-methylene-5,6,7,8-tetrahydro- quinoline-5-carbonitrile

VI-2

7-methylene-6,7-dihydro-5H-cyclo penta[b]pyridine-5-carbonitrile

VI-3

3-fluoro-8-methylene-5,6,7,8-tetra hydroquinoline-5-carbonitrile

VI-4

3-methyl-8-methylene-5,6,7,8-tetra- hydroquinoline-5-carbonitrile

IM VI-1

¹H NMR (CDCl₃) delta 8.57 (1H, dd, J=4.2, 1.8 Hz), 7.73 (1H, dd, J=7.9,1.8 Hz), 7.23 (1H, dd, J=7.9, 4.2 Hz), 6.38 (1H, d, J=1.8 Hz), 5.25 (1H,d, J=1.8 Hz), 4.07 (1H, dd, J=7.9, 4.9 Hz), 2.92 (1H, m), 2.70 (1H, m),2.32-2.15 (2H, m).

MS (ESI) m/z: 171.1 (M+H)⁺.

IM VI-2

¹H NMR (CDCl₃) delta 8.60 (1H, br d, J=5.3 Hz), 7.81 (1H, dd, J=7.9, 1.3Hz), 7.26 (1H, dd, J=7.9, 5.3 Hz), 6.11 (1 H, br t, J=2.0 Hz), 5.51 (1H, br t, J=2.0 Hz), 4.22 (1H, dd, J=8.6, 5.9 Hz), 3.34 (1H, m), 3.17(1H, m).

MS (ESI) m/z: 157.2 (M+H)⁺.

IM VI-3

¹H NMR (CDCl₃) delta 8.44 (1H, d, J=15.9, 3.1 Hz), 7.47 (1H, dd, J=8.6,3.1 Hz), 6.28 (1H, d, J=1.2 Hz), 5.24 (1 H, d, 1.2 Hz), 4.07 (1H, dd,J=8.6, 4.9 Hz), 2.94-2.87 (1H, m), 2.73-2.64 (1H, m), 2.34-2.27 (1H, m),2.23-2.15 (1H, m).

MS (ESI) m/z: 189.1 (M+H)⁺.

IM VI-4

¹H NMR (CDCl₃) delta 8.38 (1H, d, J=1.2 Hz), 7.52 (1H, d, J=1.2 Hz),6.29 (1H, d, J=1.2 Hz), 5.18 (1H, d, J=1.2 Hz), 4.02 (1H, m), 2.88 (1H,m), 2.66 (1H, m), 2.36 (3 H, s), 2.31 (1H, m), 2.17 (1H, m).

MS (ESI) m/z: 185.2 (M+H)⁺.

General Procedure: Scheme 2, Step 3 To a solution of substrate (1.0 eq.)in MeOH (0.2 M) was added TMSCl (30 eq.) at ambient temperature. Themixture was heated at reflux until complete reaction, and then cooled toroom temperature. The mixture was basified with aq. NaHCO₃ and themixture was concentrated in vacuo to remove volatile. The resultingresidue was extracted with EtOAc twice and washed with brine. Theextracts were combined, dried over Na₂SO₄, and concentrated in vacuo.The resulting residue was purified by silica gel column chromatographyto afford the following intermediates (Table 3).

TABLE 3 Intermediates Structure Chemical Name Substrate II-e-1-1

methyl 8-methylene-5,6,7,8-tetrahydro- quinoline-5-carboxylate

II-e-1-2

methyl 7-methylene-6,7-dihydro-5H-cyclo penta[b]pyridine-5-carboxylate

II-e-1-3

methyl 3-fluoro-8-methylene-5,6,7,8-tetra hydroquinoline-5-carboxylate

II-e-1-4

methyl 3-methyl-8-methylene-5,6,7,8-tetra- hydroquinoline-5-carboxylate

IM II-e-1-1

¹H NMR (CDCl₃) delta 8.51 (1H, dd, J=4.3, 1.8 Hz), 7.52 (1H, dd, J=7.9,1.8 Hz), 7.14 (1H, dd, J=7.9, 4.3 Hz), 6.29 (1H, d, J=1.8 Hz), 5.18 (1H,d, J=1.8 Hz), 3.88 (1H, dd, J=5.5, 5.5 Hz), 3.73 (3H, s), 2.81 (1H, m),2.65 (1H, m), 2.30 (1H, in), 2.07 (1H, m).

MS (ESI) m/z: 204.1 (M+H)⁺.

IM II-e-1-2

¹H NMR (CDCl₃) delta 8.52 (1H, dd, J=4.9, 1.8 Hz), 7.79 (1H, dd, J=7.3,1.8 Hz), 7.16 (1H, dd, J=7.3, 4.9 Hz), 6.04 (1H, br t, J=2.4 Hz), 5.25(1H, br t, J=2.4 Hz), 4.13 (1H, dd, J=9.2, 5.5 Hz), 3.76 (3H, s), 3.27(1H, m), 3.09 (1H, m).

MS (ESI) m/z: 190.2 (M+H)⁺.

IM II-e-1-3

¹H NMR (CDCl₃) delta 8.35 (1H, dd, J=15.3, 3.1 Hz), 7.26 (1H, dd, J=7.9,3.1 Hz), 6.19 (1 H, s),5.15 (1 H, d, J=1.8 Hz), 3.87 (1 H, dd, J=5.5,5.5 Hz),3.73 (3 H, s), 2.77 (1H, m), 2.63 (1H, m), 2.28 (1H, m), 2.06(1H, m).

MS (ESI) m/z: 222.1 (M+H)⁺.

IM II-e-1-4

¹H NMR (CDCl₃) delta 8.32 (1 H, br s), 7.29 (1 H, br s), 6.21 (1 H, brs), 5.10 (1 H, br s), 3.83 (1H, m), 3.71 (3 H, s), 2.78 (1H, m), 2.60(1H, m), 2.30 (3 H, s), 2.24 (1 H, m), 2.03 (1H, m).

MS (ESI) m/z: 218.1 (M+H)⁺.

General Procedure: Scheme 2, Step 4-A

To a stirred solution of substrate (1.0 eq.) in THF was added 1.1 M THFsolution of NaHMDS (1.3 eq.) at −78° C. under N₂ atmosphere. After beingstirred at −78° C. for 30 min, NFSI (1.3 eq.) was added to the mixture.The mixture was stirred at −78° C. until complete reaction and thenwarmed to room temperature. The mixture was poured into water andextracted with EtOAc. The extract was dried over Na₂SO₄ and concentratedin vacuo. The resulting residue was purified by silica gel columnchromatography to afford the following intermediates (Table 4).

General Procedure: Scheme 2, Step 4-B To a stirred solution of substrate(1.0 eq.) in THF was added 1.1 M THF solution of NaHMDS (1.2 eq.) at 0°C. under N₂ atmosphere. After being stirred at 0° C. for 20 min, Tognireagent (1.2 eq.) in THF was added to the mixture. The mixture waswarmed to room temperature and stirred until complete reaction. Themixture was poured into water and extracted with EtOAc. The extract wasdried over Na₂SO₄, and concentrated in vacuo. The residue was purifiedby silica gel column chromatography to afford the followingintermediates (Table 4).

TABLE 4 General Procedure: Intermediates Structure Chemical NameSubstrate Step 4 II-e-2-1

methyl 5-fluoro-8-methylene-5,6,7,8-tetra- hydroquinoline-5-carboxylate

A II-e-2-2

methyl 5-fluoro-7-methylene-6,7-dihydro- 5H-cyclopenta[b]pyridine-5-carboxylate

A II-e-2-3

methyl 3,5-difluoro-8-methylene-5,6,7,8-tetrahydroquinoline-5-carboxylate

A II-e-2-4

methyl 5-fluoro-3-methyl-8-methylene-5, 6,7,8-tetrahydroquinoline-5-carboxylate

A II-e-2-5

methyl 5-hydroxy-8-methylene-5,6,7,8- tetrahydroquinoline-5-carboxylate

B

IM II-e-2-1

¹H NMR (CDCl₃) delta 8.63 (1H, ddd, J=4.3, 1.8, 1.2 Hz), 7.68 (1H, dd,J=7.9, 1.8 Hz), 7.24 (1H, ddd, J=7.9, 4.3, 1.8 Hz), 6.37 (1 H, br s),5.31 (1H, d, J=1.2 Hz), 3.81 (3 H, s), 2.89-2.73 (2H, m), 2.48 (1H, m),2.32 (1H, m).

MS (ESI) m/z: 222.1 (M+H)⁺.

IM II-e-2-2

¹H NMR (CDCl₃) delta 8.70 (1H, ddd, J=4.9, 1.8, 1.2 Hz), 7.83 (1H, ddd,J=7.9, 1.8, 1.2 Hz), 7.27 (1H, dd, J=7.9, 4.9 Hz), 6.20 (1 H, br t,J=2.4 Hz), 5.36 (1H, dd, J=1.8, 1.2 Hz), 3.83 (3 H, s), 3.58 (1H, m),3.20 (1H, m).

MS (ESI) m/z: 208.2 (M+H)⁺.

IM II-e-2-3

¹H NMR (CDCl₃) delta 8.48 (1H, m), 7.42 (1H, dd, J=8.6, 1.8 Hz), 6.27 (1H, s), 5.28 (1H, s), 3.83 (3H, s), 2.82 (2H, m), 2.45 (1H, m), 2.29 (1H,m).

MS (ESI) m/z: 240.0 (M+H)⁺.

IM II-e-2-4

¹H NMR (CDCl₃) delta 8.37 (1 H, br s), 7.36 (1 H, br s), 6.23 (1 H, brs), 5.19 (1 H, br s), 3.76 (3 H, s), 3.73 (1H, m), 2.40-2.24 (2H, m),2.30 (3 H, s), 2.08 (1H, m).

MS (ESI) m/z: 236.2 (M+H)⁺.

IM II-e-2-5

¹H NMR (CDCl₃) delta 8.55 (1H, dd, J=4.6, 2.0 Hz), 7.55 (1H, dd, J=7.9,2.0 Hz), 7.19 (1H, dd, J=7.9, 4.6 Hz), 6.31 (1 H, br s), 5.26 (1H, d,J=2.0 Hz), 3.93 (1 H, br), 3.77 (3 H, s), 2.92-2.73 (2H, m), 2.30 (1H,ddd, J=13.2, 8.6, 4.3 Hz), 2.10 (1 H, ddd, J=13.2, 7.9, 4.6 Hz).

MS (ESI) m/z: 220.2 (M+H)⁺.

General Procedure: Scheme 2, Step 5

O₃ was bubbled into a solution of substrate (1.0 eq.) in 50% CH₂Cl₂-MeOHat −78° C. until starting material consumed. N₂ was bubbled into themixture to remove the excess of O₃ at −78° C. The mixture was quenchedwith Me₂S (2.0 eq.) and the mixture was warmed to room temperature. Themixture was concentrated in vacuo and the resulting residue was purifiedby silica gel column chromatography to afford the followingIntermediates (Table 5).

TABLE 5 Intermediates Structure Chemical Name Substrate II-c-1

methyl 8-oxo-5,6,7,8-tetrahydroquinoline- 5-carboxylate

II-c-2

methyl 5-fluoro-8-oxo-5,6,7,8-tetrahydro- quinoline-5-carboxylate

II-c-3

methyl 3,5-difluoro-8-oxo-5,6,7,8-tetra- hydroquinoline-5-carboxylate

II-c-4

methyl 5-fluoro-3-methyl-8-oxo-5,6,7,8-tetrahydroquinoline-5-carboxylate

IM II-c-1

¹H NMR (CDCl₃) delta 8.79 (1H, dd, J=4.6, 1.3 Hz), 7.78 (1H, br d, J=7.9Hz), 7.46 (1H, dd, J=7.9, 4.6 Hz), 4.05 (1H, dd, J=5.2, 4.6 Hz), 3.76 (3H, s),3.04 (1H, in), 2.82 (1H, m), 2.59 (1H, m), 2.43 (1H, m).

MS (EST) m/z: 206.1 (M+H)⁺.

IM II-c-2

¹H NMR (CDCl₃) delta 8.91 (1H, dd, J=4.3, 1.2 Hz), 7.96 (1H, dd, J=7.9,1.2 Hz), 7.57 (1H, dd, J=7.9, 4.3 Hz), 3.85 (3 H, s), 3.06-3.03 (2H, m),2.85 (1H, m), 2.63 (1H, m).

MS (ESI) m/z: 224.1 (M+H)⁺.

IM II-c-3

¹H NMR (CDCl₃) delta 8.73 (1H, dd, J=14.6, 2.4 Hz), 7.66 (1H, dd, J=7.9,2.4 Hz), 3.86 (3 H, s), 3.06-2.99 (2 H, m), 2.85 (1H, m), 2.62 (1H, m).MS (ESI) m/z: 242.0 (M+H)⁺.

IM II-c-4

¹H NMR (CDCl₃) delta 8.72 (1H, d, J=1.4 Hz), 7.73 (1H, d, J=1.4 Hz),3.86 (3 H, s), 3.03-2.99 (2H, m), 2.82 (1H, m), 2.61 (1H, m), 2.48 (3 H,s). MS (ESI) m/z: 238.2 (M+H)⁺.

General Procedure: Scheme 2, Step 6

NaBH₄ (1.5 eq.) was added to a solution of substrate (1.0 eq.) in MeOHand the mixture was stirred at room temperature until complete reaction.The mixture was poured into water and extracted with EtOAc. The extractwas dried over Na₂SO₄ and concentrated in vacuo. The resulting residuewas purified by silica gel column chromatography to afford the followingintermediates (Table 6).

TABLE 6 Intermediates Structure Chemical Name Substrate II-d-1

methyl 8-hydroxy-5,6,7,8-tetrahydro- quinoline-5-carboxylate

II-d-2

methyl 5-fluoro-8-hydroxy-5,6,7,8-tetra- hydroquinoline-5-carboxylate

IM II-d-1

¹H NMR (CDCl₃) delta 8.49 (1H, d, J=4.6 Hz), 7.61 (0.5 H, d, J=7.9 Hz),7.57 (0.5 H, d, J=7.9 Hz), 7.20 (1H, dd, J=7.9, 5.3 Hz), 4.75 (0.5 H,dd, J=8.6, 5.3 Hz), 4.67 (0.5 H, dd, J=9.3, 5.3 Hz), 4.10 (1 H, br),3.91 (0.5 H, dd, J=7.9, 6.6 Hz), 3.82 (0.5 H, br), 3.75 (1.5 H, s), 3.72(1.5 H, s), 2.44-1.99 (3.5 H, m), 1.81 (0.5 H, m).

MS (ESI) m/z: 208.2 (M+H)⁺.

IM II-d-2

¹H NMR (CDCl₃) delta 8.64 (1H, dd, J=4.6, 1.3 Hz), 7.80 (0.5 H, d, J=8.6Hz), 7.69 (0.5 H, dd, J=7.9, 1.3 Hz), 7.31 (1H, dd, J=7.9, 4.6 Hz),4.80-4.71 (1H, m), 4.31 (0.5 H, br), 3.84 (2 H, s), 3.80 (1.5 H, s),2.75-2.63 (0.5 H, m), 2.53-2.00 (3.5 H, m).

MS (ESI) m/z: 226.2 (M+H)⁺.

General Procedure: Scheme 3, Step 1

To a stirred solution of tert-butyl 2-(diethoxyphosphoryl)acetate (1.0eq.) in THF was added NaH (60% oil dispersant, 1.0 eq.) at 0° C. Afterbeing stirred at this temperature for 1 h, a solution of substrate (1.0eq.) in THF was added to the mixture. The mixture was warmed to roomtemperature and stirred until complete reaction. The reaction mixturewas poured into water and extracted with EtOAc. The extract was driedover Na₂SO₄ and concentrated in vacuo. The resulting residue waspurified by silica gel column chromatography to afford the followingintermediates (Table 7).

TABLE 7 Intermediates Structure Chemical Name Substrate VII-1

methyl 8-(2-(tert-butoxy)-2-oxoethylidene)-5,6,7,8-tetrahydroquinoline-5- carboxylate

VII-2

methyl 8-(2-(tert-butoxy)-2-oxoethylidene)-5-fluoro-5,6,7,8-tetrahydroquinoline- 5-carboxylate

IM VII-1; isomer A

¹H NMR (CDCl₃) delta 8.54 (1H, dd, J=4.6, 1.3 Hz), 7.54 (1H, br d, J=7.9Hz), 7.23 (1H, dd, J=7.9, 4.6 Hz), 7.15 (1 H, s), 3.87 (1H, t, J=5.3Hz), 3.72 (3 H, s), 3.39 (1H, m), 3.19 (1H, m), 2.29 (1H, m), 2.05 (1H,m), 1.51 (9 H, s).

MS (ESI) m/z: 304.2 (M+H)⁺.

IM VII-1; isomer B

¹H NMR (CDCl₃) delta 8.42 (1H, dd, J=4.6, 1.3 Hz), 7.54 (1H, br d, J=7.9Hz), 7.15 (1H, dd, J=7.9, 4.6 Hz), 5.86 (1 H, s), 3.86 (1H, t, J=5.3Hz), 3.70 (3 H, s), 2.80 (1H, m), 2.56 (1H, m), 2.32 (1H, m), 2.13 (1H,m), 1.56 (9 H, s).

MS (ESI) m/z: 304.2 (M+H)⁺.

IM VII-2

¹H NMR (CDCl₃) delta 8.65 (0.25 H, br d, J=3.3 Hz), 8.54 (0.75 H, dd,J=4.6, 2.0 Hz), 7.77 (0.25 H, br d, J=7.9 Hz), 7.69 (0.75 H, br d, J=7.3Hz), 7.33 (0.25 H, dd, J=7.9, 4.6 Hz), 7.24 (0.75 H, br d, J=4.6 Hz),5.98 (0.75 H, s), 5.30 (0.25 H, s), 3.81 (0.75 H, s), 3.80 (2.25 H, s),3.42 (0.5 H, m), 2.78 (1.5 H, m), 2.30-2.10 (2H, m), 1.58 (6.75 H, s),1.52 (2.25 H, s).

MS (ESI) m/z: 322.1 (M+H)⁺.

General Procedure: Scheme 3, Step 2

10% Pd-C (0.2 eq.) was added to a solution of substrate (1.0 eq.) inMeOH and the mixture was stirred until complete reaction at roomtemperature under H₂ atmosphere. The reaction mixture was filtratedthrough a pad of cerite and the filtrate was concentrated in vacuo. Theresulting residue was purified by silica gel column chromatography toafford the following intermediates (Table 8).

TABLE 8 Intermediates Structure Chemical Name Substrate II-v-1

methyl 8-(2-(tert-butoxy)-2-oxoethyl)-5,6, 7,8-tetrahydroquinoline-5-carboxylate

II-v-2

methyl 8-(2-(tert-butoxy)-2-oxoethyl)-5-fluoro-5,6,7,8-tetrahydroquinoline- 5-carboxylate

IM II-v-1

¹H NMR (CDCl₃) delta 8.45 (1H, dd, J=4.6, 1.3 Hz), 7.50 (1H, br d, J=7.3Hz), 7.09 (1H, dd, J=7.3, 4.6 Hz), 3.81 (1H, t, J=5.3 Hz), 3.72 (3 H,s), 3.34 (1H, m), 3.13 (1H, dd, J=10.5, 4.6 Hz), 2.41 (1H, dd, J=15.8,9.9 Hz), 2.31-1.72 (4H, m), 1.46 (9 H, s).

MS (ESI) m/z: 306.1 (M+H)⁺.

IM II-v-2

¹H NMR (CDCl₃) delta 8.58 (0.5 H, d, J=4.6 Hz), 8.49 (0.5 H, d, J=4.6Hz), 7.70 (0.5 H, d, J=7.3 Hz), 7.53 (0.5 H, d, J=7.9 Hz), 7.20 (0.5 H,dd, J=7.9, 4.6 Hz), 7.13 (0.5 H, dd, J=7.3, 4.6 Hz), 3.83 (1H, t, J=5.3Hz), 3.74 (1.5 H, s), 3.72 (1.5 H, s), 3.55-3.30 (1H, m), 3.15-2.94 (1H,m), 2.57-2.41 (1H, m), 2.4-1.7 (3H, m), 1.47 (4.5 H, s), 1.45 (4.5 H,s).

MS (EST) m/z: 324.1 (M+H)⁺.

Preparation of Intermediates III

General Procedure: Scheme 5, Step 1

To a solution of the substrate (1.0 eq.) in CCl₄ were added NBS (1.2eq.) and AIBN (0.1 eq.) at 50° C. under N₂ atmosphere. The reactionmixture was heated at reflux and stirred for 2 h, another portion ofAIBN (0.1 eq.) was added to the mixture. After being stirred at refluxfor 16 h, the mixture was cooled to room temperature. The mixture wasconcentrated in vacuo and diethylether was added to the resultingresidue. The insoluble materials were removed by filtration. Thefiltrate was washed with 2 N hydrochloric acid and brine. The extractwas dried over Na₂SO₄ and concentrated in vacuo. The resulting residuewas purified and separated by column chromatography to afford thefollowing intermediates, di-bromide IX and mono-bromide X (Table 9).

TABLE 9 Intermediates Structure Chemical Name Substrate IX-1

2,4-dichloro-6-(dibromomethyl) benzonitrile

X-1

2-(bromomethyl)-4,6-dichloro- benzonitrile IX-2

2-chloro-6-(dibromomethyl)-4- fluorobenzonitrile

X-2

2(bromomethyl)-6-chloro-4- fluorobenzonitrile

IM IX1

¹H NMR (CDCl₃) delta 7.93 (1H, d, J=2.0 Hz), 7.52 (1H, d, J=2.0 Hz),6.90 (1 H, s).

IM X-1

¹H NMR (CDCl₃) delta 7.49 (1H, d, J=2.0 Hz), 7.47 (1H, d, J=2.0 Hz),4.57 (2 H, s).

IM IX-2

¹H NMR (CDCl₃) delta 7.69 (1H, dd, J=9.2, 2.4 Hz), 7.26 (1H, dd, J=9.2,2.4 Hz), 6.93 (1H, d, J=1.2 Hz).

IM X-2

¹H NMR (CDCl₃) delta 7.23 (1H, dd, J=7.9, 2.4 Hz), 7.22 (1H, dd, J=7.9,2.4 Hz), 4.59 (2 H, s).

MS (ESI) m/z: 250.9 (M+H)⁺.

Procedure: Scheme 5, Step 2

Intermediate (IM) XI-1, 2,4-dichloro-6-(difluoromethyl)benzonitrile

To a solution of 2,4-dichloro-6-(dibromomethyl)benzonitrile (350 mg,1.018 mmol, IM IX-1) in CH₂Cl₂ (5 mL) was added silver tetrafluoroborate(495 mg, 2.54 mmol) at ambient temperature under N₂ atmosphere. Afterbeing stirred at room temperature for 3 h, the insoluble material wasremoved by filtration. The filtrate was concentrated in vacuo to afford204 mg (90%) of the title compound.

¹H NMR (CDCl₃) delta 7.68 (2 H, br s), 6.89 (1H, dd, J=54.7, 54.0 Hz).

Procedure: Scheme 5, Step 4

Intermediate (IM) XII-1, 3-chloro-2-cyano-5-fluorobenzyl acetate

To a solution of the 2-(bromomethyl)-4,6-dichlorobenzonitrile (609 mg,2.451 mmol, IM X-2) in AcOH (6.0 mL) was added NaOAc (1.0 g, 12.25 mmol)at ambient temperature. The mixture was heated at 100° C. for 6 h. Themixture was concentrated in vacuo and aq. NaHCO₃ was added to theresulting residue. The mixture was extracted with EtOAc and washed withbrine. The extracts were dried over Na₂SO₄ and concentrated in vacuo.The resulting residue was purified by silica gel column chromatography(5% EtOAc/n-hexane) to afford 505 mg (91%) of the title compound. MS(ESI) m/z: 245.0 (M+H₃O)⁺.

General Procedure: Scheme 5, Step 3

To a solution of the substrate (1.0 eq.) in AcOH was added NaOAc (5.0eq.) at ambient temperature. The resulting mixture was heated at 100° C.until complete reaction. The mixture was concentrated in vacuo and aq.NaHCO₃ was added to the resulting residue. The mixture was extractedwith EtOAc and washed with brine. The extracts were dried over Na₂SO₄and concentrated in vacuo. The resulting residue was purified by silicagel column chromatography to afford the following intermediates (Table10).

TABLE 10 Intermediates Structure Chemical Name Substrate III-a-1

(2,4-dichloro-6-(difluoromethyl) phenyl)methanamine

III-b-1

(2-(aminomethyl)-3-chloro-5- fluorophenyl)methanol

IM III-a-1

¹H NMR (CDCl₃) delta 7.53 (1 H, br s), 7.48 (1 H, br s), 6.91 (1H, dd,J=82.0, 81.0 Hz), 4.02 (2 H, s), 1.48 (2 H, s).

MS (ESI) m/z: 226.0 (M+H)⁺.

IM III-b-1

¹H NMR (CDCl₃) delta 7.09 (1H, dd, J=8.6, 2.4 Hz), 7.03 (1H, dd, J=8.6,2.4 Hz), 4.64 (2H, s), 4.16 (2H, s), 2.35 (3 H, br).

MS (ESI) m/z: 190.1 (M+H)⁺.

The following Examples and Intermediates were prepared by GeneralProcedure A (Tables 11 and 13).

General Procedure A

A mixture of substrate (1.0 eq.) and 2 N aq. NaOH (2.0 eq.) in MeOH wasstirred at room temperature for 1.5 h, 2 N hydrochloric acid (2.2 eq.)was added to the mixture. The mixture was concentrated in vacuo toafford a glass. Toluene and MeCN were added to the mixture andconcentrated in vacuo. This procedure was repeated 3 times to removeremaining water. The residual powder was dissolved with DMF and amine(1.5 eq.), triethylamine (3.0 eq.), and HBTU (1.3 eq.) were added to themixture at ambient temperature. After overnight stirring, the mixturewas poured into water and the mixture was extracted with CH₂Cl₂. Theextract was concentrated in vacuo and the resulting residue was purifiedby silica gel column chromatography, and/or SCX cartridge column,preparative HPLC to afford the following Examples and Intermediates.

TABLE 11 Examples Structure Chemical Name Substrate Amine 1

N-(2,4-dichloro-6-methyl- benzyl)-8-oxo-5,6,7,8- tetrahydroquinoline-5-carboxamide

2

N-(2-chloro-3-(trifluoro methyl)benzyl)-8-oxo-5,6,7,8-tetrahydroquinoline- 5-carboxamide

3

N-(2,3-dichlorobenzyl)- 8-oxo-5,6,7,8-tetrahydro-quinoline-5-carboxamide

4

N-(2,4-dichloro-6-(hydroxy- methyl)benzyl)-8-oxo-5,6,7,8-tetrahydroquinoline- 5-carboxamide

5

N-(cycloheptylmethyl)- 8-oxo-5,6,7,8-tetrahydro- quinoline-5-carboxamide

6

N-(2,4-dichloro-6-methyl- benzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline- 5-carboxamide

7

N-(2-chloro-3-(trifluoro methyl)benzyl)-8-hydroxy- 5,6,7,8-tetrahydro-quinoline-5-carboxamide

8

N-(2,3-dichlorobenzyl)- 8-hydroxy-5,6,7,8-tetra hydroquinoline-5-carboxamide

9

N-(2,4-dichloro-6-(hydroxy- methyl)benzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline- carboxamide

10

N-(2,4-dichloro-6-(methoxy- methyl)benzyl)-8-hydroxy-5,6,7,8-tetrahydro- quinoline-5-carboxamide

11

N-(2,4-dichloro-6-methyl- benzyl)-7-methylene- 6,7-dihydro-5H-cyclopenta[b]pyridine-5-carboxamide

TABLE 12 LC MS Examples Method tR (min) [M + H]⁺ 1 D 1.53 363.0 2 D 1.47383.0 3 D 1.40 349.0 4 A 1.25 379.3 5 D 1.45 301.2 6 D 1.53 365.0 7 D1.46 385.0 8 D 1.40 351.0 9 A 1.26 381.3 10 A 1.44 395.1 11 D 1.79 347.0

Ex 2

¹H NMR (DMSO d6) delta 9.00 (1 H, br), 8.67 (1 H, m),7.79 (2H, br d,J=7.9 Hz), 7.68 (1 H, d, J=7.3 Hz), 7.68-7.54 (2 H, m), 4.48 (2 H, m),4.12 (1H, dd, J=5.9, 5.2 Hz), 2.84 (1H, m), 2.66 (1H, m), 2.38-2.32 (2H,m).

Ex 6

¹H NMR (DMSO d6) delta 8.42 (1H, d, J=4.6 Hz), 8.37 (1 H, br), 7.50 (1H, s), 7.40-7.36 (2H, m), 7.23 (1H, dd, J=7.9, 4.6 Hz), 5.18 (0.7 H, d,J=4.0 Hz), 5.13 (0.3 H, d, J=4.0 Hz), 4.51 (1 H, br), 4.44 (0.7 H, s),4.42 (0.7 H, s), 4.39 (0.3 H, s), 4.37 (0.3 H, s), 3.74 (0.3 H, br),3.65 (0.7 H, br), 2.40 (2.1 H, s), 2.37 (0.9 H, s), 2.20-1.90 (2H, m),1.82-1.76 (2H, m).

Ex 7

¹H NMR (DMSO d6) delta 8.79 (1 H, br), 8.43 (1H, d, J=4.6 Hz), 7.80 (1H,d, J=7.9 Hz), 7.68 (1H, dd, J=8.6, 6.6 Hz), 7.58 (1H, dd, J=7.9, 7.3Hz), 7.46 (1 H, d, J=7.3 Hz), 7.23 (1H, dd, J=8.6, 5.3 Hz), 5.18 (1 H,br), 4.54 (1 H, br), 4.47 (2H, m), 3.75 (1H, m), 2.22-1.80 (4H, m).

TABLE 13 Inter- mediates Structure Chemical Name Substrate Amine I-e-1

N-(2,4-dichloro-6- methyl)benzyl)-8- methylene-5, 6,7,8-tetrahydro-quinoline- 5-carboxamide

I-e-2

N-(2-chloro-3- (trifluoromethyl) benzyl)-8-methylene-5,6,7,8-tetrahydro- quinoline-5- carboxamide

I-e-3

N-(2-chloro-3- (trifluoromethyl) benzyl)-5-fluoro- 8-methylene-5,6,7,8-tetrahydroquinoline-5- carboxamide

I-e-4

N-(2,4-dichloro-6- methylbenzyl)-5- hydroxy-8- methylene-5,6,7,8-tetrahydroquinoline- 5-carboxamide

I-e-5

N-(2-chloro-3- (trifluoromethyl) benzyl)-5-hydroxy- 8-methylene-5,6,7,8-tetrahydroquinoline-5- carboxamide

I-e-6

N-(2,4-dichloro- benzyl)-8-methylene- 5,6,7,8-tetra- hydroquinoline-5-carboxamide

I-e-7

N-(2-chloro-4- fluorobenzyl)- 8-methylene-5,6,7,8- tetrahydroquinoline-5-carboxamide

I-e-8

N-(2,4-dichloro-6- fluorobenzyl)-8- methylene-5,6,7,8-tetrahydroquinoline- 5-carboxamide

I-e-9

8-methylene-N-(2,3, 4-trifluorobenzyl)- 5,6,7,8-tetrahydro- quinoline-5-carboxamide

I-e-10

8-methylene-N-(2,4, 6-trifluorobenzyl)-5,6,7,8-tetrahydro- quinoline-5-carboxamide

I-e-11

N-(2,4-difluorobenzyl)- 8-methylene-5,6,7,8- tetrahydroquinoline-5-carboxamide

I-e-12

N-(4-fluoro-2- (trifluoromethyl) benzyl)-8- methylene-5,6,7,8-tetrahydroquinoline- 5-carboxamide

I-e-13

N-(4-chloro-2- fluorobenzyl)- 8-methylene-5,6,7,8- tetrahydroquinoline-5-carboxamide

I-e-14

N-(4-bromo-2- fluorobenzyl)- 8-methylene-5,6,7, 8-tetrahydroquinoline-5-carboxamide

I-e-15

N-(2-chloro-3,4- difluorobenzyl)-8- methylene-5,6,7,8-tetrahydroquinoline- 5-carboxamide

I-e-16

N-(2,4-dichloro-6- methylbenzyl)-5- fluoro-8-methylene- 5,6,7,8-tetra-hydroquinoline-5- carboxamide

I-e-17

N-(2,4-dichloro-6- (hydroxymethyl) benzyl)-5-fluoro-8-methylene-5,6,7,8- tetrahydroquinoline- 5-carboxamide

I-e-18

N-(2,3-dichloro- benzyl)- 5-(fluoro-8- methylene-5, 6,7,8-tetrahydro-quinoline- 5-carboxamide

I-e-19

N-(2,4-dichloro- benzyl)-5-fluoro-8- methylene-5, 6,7,8-tetrahydro-quinoline- 5-carboxamide

I-e-20

N-(2-chloro-4- fluorobenzyl)- 5-fluoro-8-methylene- 5,6,7,8-tetrahydroquinoline- 5-carboxamide

I-e-21

N-(2,4-dichloro-6- (methoxymethyl) benzyl)-5-fluoro 8-methylene-5,6,7,8tetrahydroquinoline-5- carboxamide

I-e-22

N-(2-chloro-3- (trifluoromethyl) benzyl)-7-methylene- 6,7-dihydro-5H-cyclopenta[b]pyridine- 5-carboxamide

I-e-23

N-(2,3-dichloro- benzyl)-7-methylene- 6,7-dihydro- 5H-cyclopenta[b]pyridine-5- carboxamide

I-e-24

N-(2,4-dichloro- benzyl)-5-fluoro-7- methylene-6,7-dihydro-5H-cyclopenta[b] pyridine-5-carboxamide

I-v-1

tert-butyl 2-(5-((2,4-dichloro-6- methylbenzyl) carbamoyl)-5,6,7,8-tetrahydroquinolin- 8-yl)acetate

I-v-2

tert-butyl 2-(5-((2-chloro-3- (trifluoromethyl) benzyl)carbamoyl)-5,6,7,8-tetrahydro quinolin-8-yl)acetate

I-v-3

tert-butyl 2-(5-((2,4-dichloro- 6-methylbenzyl) carbamoyl)-5-fluoro-5,6,7,8- tetrahydroquinolin- 8-yl)acetate

IM I-e-1

¹H NMR (CDCl₃) delta 8.54 (1H, dd, J=4.6, 2.0 Hz), 7.40 (1H, d, J=9.2Hz), 7.21 (1H, d, J=2.0 Hz), 7.15 (1H, dd, J=9.2, 4.6 Hz), 7.09 (1H, d,J=2.0 Hz), 6.31 (1 H, s),5.66 (1H, br), 5.19 (1H, s), 4.56 (1H, dd,J=14.5, 5.9 Hz), 4.44 (1H, dd, J=14.5, 5.9 Hz), 3.71 (1 H, br t, J=5.3Hz), 2.63 (2H, m), 2.45 (3 H, s), 2.35 (1H, m), 2.04 (1H, m).

MS (ESI) m/z: 361.7 (M+H)⁺.

IM I-e-2

¹H NMR (CDCl₃) delta 8.56 (1H, d, J=4.6 Hz), 7.64 (1H, d, J=7.3 Hz),7.55 (1H, d, J=7.3 Hz),7.42 (1H, d, J=8.6 Hz), 7.35 (1H, br t, J=7.3Hz),7.17 (1H, dd, J=7.3, 4.6 Hz), 6.34 (1H, s), 5.86 (1H, br), 5.22 (1H,s), 4.59 (1H, dd, J=14.5, 5.9 Hz), 4.51 (1H, dd, J=14.5, 5.9 Hz), 3.77(1 H, br t, J=5.3 Hz), 2.66 (2H, m), 2.18 (1 H, m), 2.06 (1H, m).

MS (ESI) m/z: 381.7 (M+H)⁺.

IM I-e-3

¹H NMR (CDCl₃) delta 8.60 (1 H, br dd, J=4.6, 1.3 Hz), 7.70 (1H, d,J=7.9 Hz), 7.65 (1H, d, J=7.3 Hz), 7.47 (1 H, br dd, J=7.9, 1.3 Hz),7.40 (1H, dd, J=7.9, 7.3 Hz), 7.30 (1 H, br), 7.18 (1H, dd, J=7.9, 4.6Hz), 6.35 (1 H, br s), 5.31 (1H, d, J=2.6 Hz), 4.73 (2H, d, J=5.9 Hz),2.88-2.83 (2H, m), 2.60-2.20 (2H, m).

MS (ESI) m/z: 399.0 (M+H)⁺.

IM T-e-4

¹H NMR (DMSO d6) delta 8.48 (1H, dd, J=4.6, 2.0 Hz), 8.12 (1 H, br t,J=5.3 Hz), 7.53 (1H, dd, J=7.9, 2.0 Hz), 7.47 (1H, d, J=2.0 Hz), 7.32(1H, d, J=2.0 Hz), 7.26 (1H, dd, J=7.9, 4.6 Hz), 6.26 (1H, s), 6.18 (1H,s), 5.15 (1 H, br), 4.44 (2H, d, J=5.3 Hz), 2.74 (2H, m), 2.40 (3 H, s),2.15 (1H, m), 1.86 (1H, m).

MS (ESI) m/z: 377.3 (M+H)⁺.

IM I-e-5

¹H NMR (DMSO d6) delta 8.90 (1 H, br t, J=6.6 Hz), 8.49 (1H, dd, J=4.6,2.0 Hz), 7.78 (1H, br d, J=7.9 Hz), 7.67-7.54 (3H, m), 7.29 (1H, dd,J=7.9, 4.6 Hz), 6.43 (1 H, s), 6.18 (1 H, br s), 5.17 (1 H, br s), 4.47(2H, d, J=6.6 Hz), 2.78 (2H, m), 2.23 (1H, m), 1.96 (1H, m).

MS (ESI) m/z: 397.3 (M+H)⁺.

IM I-e-6

¹H NMR (CDCl₃) delta 8.55 (1H, dd, J=4.9, 1.8 Hz), 7.43 (1H, dd, J=7.9,1.8 Hz), 7.36 (1H, d, J=2.4 Hz), 7.30-7.26 (1H, m), 7.21 (1H, dd, J=7.9,4.9 Hz), 7.17 (1H, dd, J=8.0, 4.9 Hz), 6.33 (1H, d, J=1.8 Hz), 5.77 (1H,br), 5.21 (1H, d, J=1.8 Hz), 4.47 (1H, dd, J=15.3, 6.1 Hz), 4.41 (1H,dd, J=15.3, 6.1 Hz), 3.75 (1H, t, J=4.9 Hz), 3.75 (2 H, br t, J=4.9 Hz),2.34 (1H, m), 2.05 (1H, m).

MS (ESI) m/z: 346.7 (M+H)⁺.

IM I-e-7

¹H NMR (CDCl₃) delta 8.55 (1H, dd, J=4.9, 1.2 Hz), 7.43 (1H, dd, J=7.9,1.2 Hz),7.32 (1H, dd, J=8.6, 6.1 Hz), 7.16 (1H, dd, J=7.9, 4.9 Hz), 7.09(1H, dd, J=8.6, 2.4 Hz), 6.94 (1H, ddd, J=8.6, 7.9, 2.4 Hz), 6.33 (1H,d, J=1.8 Hz), 5.76 (1 H, br), 5.21 (1H, d, J=1.8 Hz), 4.47 (1H, dd,J=15.3, 6.1 Hz), 4.41 (1H, dd, J=15.3, 6.1 Hz), 3.75 (1H, t, J=4.9 Hz),2.66-2.62 (2H, m), 2.34 (1H, m), 2.05 (1H, m).

MS (ESI) m/z: 330.8 (M+H)⁺.

IM I-e-8

¹H NMR (CDCl₃) delta 8.54 (1H, dd, J=4.9, 1.8 Hz), 7.42 (1H, dd, J=7.9,1.8 Hz), 7.20 (1H, m), 7.16 (1H, dd, J=7.9, 4.9 Hz), 7.03 (1H, dd,J=9.2, 1.8 Hz), 6.32 (1H, d, J=1.8 Hz), 5.64 (1H, br), 5.20 (1H, d,J=1.8 Hz), 4.58 (1H, ddd, J=14.7, 5.5, 1.2 Hz), 4.49 (1H, dd, J=14.7,5.5, 1.8 Hz), 3.74 (1H, m), 2.65-2.61 (2H, m), 2.31 (1H, m), 2.03 (1H,m).

MS (ESI) m/z: 364.7 (M+H)⁺.

IM I-e-9

¹H NMR (CDCl₃) delta 8.46 (1H, dd, J=4.8, 1.2 Hz), 7.39 (1H, dd, J=7.9,1.2 Hz), 7.13 (1H, dd, J=7.9, 4.8 Hz), 6.99 (1H, m), 6.89 (1H, m), 6.27(1H, d, J=1.8 Hz), 6.13 (1 H, br t, J=5.5 Hz), 5.18 (1H, d, J=1.8 Hz),4.41 (2H, br d, J=6.1 Hz), 3.73 (1 H, br t, J=5.5 Hz), 2.65-2.61 (2H,m), 2.26 (1H, m), 2.03 (1H, m).

MS (ESI) m/z: 333.2 (M+H)⁺.

IM I-e-10

¹H NMR (CDCl₃) delta 8.53 (1H, dd, J=4.3, 1.2 Hz), 7.41 (1H, dd, J=7.9,1.2 Hz), 7.16 (1H, dd, J=7.9, 4.3 Hz), 6.64 (2H, m), 6.31 (1H, d, J=1.8Hz), 5.56 (1 H, br), 5.19 (1H, d, J=1.8 Hz), 4.49 (1H, dd, J=14.7, 6.1Hz), 4.43 (1H, dd, J=14.7, 5.5 Hz), 3.73 (1 H, br t, J=5.5 Hz),2.65-2.61 (2H, m), 2.31 (1H, m), 2.04 (1H, m).

MS (ESI) m/z: 333.1 (M+H)⁺.

IM I-e-11

¹H NMR (CDCl₃) delta 8.54 (1H, dd, J=4.9, 1.2 Hz), 7.42 (1H, dd, J=7.9,1.2 Hz), 7.29-7.22 (1H, m), 7.16 (1H, dd, J=7.9, 4.9 Hz), 6.85-6.74 (2H,m), 6.32 (1H, d, J=1.8 Hz), 5.66 (1 H, br), 5.20 (1H, d, J=1.8 Hz), 4.42(2H, br d, J=5.5 Hz), 3.75 (1 H, br t, J=5.5 Hz), 2.66-2.63 (2H, m),2.33 (1H, m), 2.06 (1H, m).

MS (ESI) m/z: 315.2 (M+H)⁺.

IM I-e-12

¹H NMR (CDCl₃) delta 8.48 (1H, dd, J=4.2, 1.2 Hz), 7.45 (1H, dd, J=8.6,5.5 Hz),7.38 (1H, dd, J=7.9, 1.2 Hz), 7.30 (1H, dd, J=8.6, 2.4 Hz), 7.17(1H, dt, J=8.6, 2.4 Hz), 7.12 (1H, dd, J=7.9, 4.2 Hz), 6.27 (1H, d,J=1.2 Hz), 6.07 (1 H, br t, J=6.1 Hz), 5.16 (1H, d, J=1.2 Hz), 4.51 (2H,br d, J=6.1 Hz), 3.72 (1 H, br t, J=5.5 Hz), 2.72-2.60 (2H, m), 2.27(1H, m), 2.02 (1H, m).

MS (ESI) m/z: 365.1 (M+H)⁺.

IM I-e-13

¹H NMR (CDCl₃) delta 8.44 (1H, dd, J=4.9, 1.8 Hz), 7.39 (1H, dd, J=7.9,1.8 Hz), 7.18 (1H, t, J=7.9 Hz), 7.11 (1H, dd, J=7.9, 4.9 Hz), 7.08-7.00(2H, m), 6.25 (1H, d, J=1.2 Hz), 6.17 (1H, br t, J=5.5 Hz),5.16 (1H, d,J=1.2 Hz), 4.38 (2H, br d, J=6.1 Hz), 3.71 (1 H, br t, J=5.5 Hz),2.69-2.55 (2H, m), 2.24 (1H, m), 2.02 (1 H, m).

MS (ESI) m/z: 331.1 (M+H)⁺.

IM I-e-14

¹H NMR (CDCl₃) delta 8.46 (1H, dd, J=4.9, 1.8 Hz), 7.38 (1H, dd, J=7.9,1.8 Hz), 7.22-7.10 (4H, m), 6.26 (1H, d, J=1.2 Hz), 6.16 (1 H, br t,J=5.5 Hz), 5.17 (1 H, d, J=1.2 Hz), 4.37 (2H, br d, J=5.5 Hz), 3.71 (1H, br t, J=5.5 Hz), 2.69-2.55 (2 H, m), 2.24 (1H, m), 2.02 (1H, m).

MS (ESI) m/z: 375.0 (M+H)⁺.

IM I-e-15

¹H NMR (CDCl₃) delta 8.52 (1H, dd, J=4.9, 1.8 Hz), 7.42 (1H, dd, J=7.9,1.8 Hz), 7.16 (1H, dd, J=7.9, 4.9 Hz), 7.09-7.01 (2H, m), 6.31 (1H, d,J=1.8 Hz), 5.92 (1H, br t, J=5.5 Hz),5.20 (1H, d, J=1.8 Hz), 4.47 (1H,dd, J=15.3, 6.1 Hz), 4.41 (1H, dd, J=15.5, 6.1 Hz), 3.75 (1 H, br t,J=5.5 Hz), 2.64 (2H, m), 2.31 (1H, m), 2.05 (1H, m).

MS (ESI) m/z: 349.0 (M+H)⁺.

IM I-e-16

¹H NMR (CDCl₃) delta 8.61 (1H, dd, J=4.6, 2.0 Hz), 7.47 (1H, ddd, J=7.9,2.0, 1.3 Hz),7.32 (1H, d, J=1.3 Hz), 7.19 (1H, dd, J=7.9, 4.6 Hz), 7.16(1H, d, J=1.3 Hz), 7.04 (1H, br d, J=5.3 Hz),6.34 (1H, s), 5.31 (1H, s),4.72 (1H, dd, J=13.8, 5.3 Hz), 4.63 (1H, dd, J=13.8, 5.3 Hz), 2.84 (2H,m), 2.45 (1H, m), 2.48 (3 H, s), 2.25 (1H, m).

MS (ESI) m/z: 379.0 (M+H)⁺.

IM I-e-17

¹H NMR (CDCl₃) delta 8.58 (1H, dd, J=4.6, 2.0 Hz), 7.62 (1H, br d, J=5.3Hz), 7.44 (1H, d, J=2.0 Hz), 7.40 (1H, ddd, J=7.9, 2.0, 1.3 Hz),7.34(1H, d, J=2.0 Hz), 7.16 (1H, dd, J=7.9, 4.6 Hz), 6.33 (1H, s), 5.30 (1H,s), 4.81-4.65 (4H, m), 3.96 (1 H, br), 2.80 (2H, m), 2.86-2.14 (2H, m).

MS (ESI) m/z: 394.9 (M+H)⁺.

IM I-e-18

¹H NMR (CDCl₃) delta 8.61 (1 H, br dd, J=4.6, 1.3 Hz), 7.51-7.45 (2H,m), 7.35 (1 H, dd, J=7.9, 1.3 Hz), 7.26-7.20 (2H, m), 7.19 (1H, dd,J=7.9, 4.6 Hz), 6.35 (1H, s), 5.31 (1H, s), 4.69 (1H, d, J=5.9 Hz),2.88-2.83 (2H, m), 2.61-2.20 (2H, m).

MS (ESI) m/z: 364.9 (M+H)⁺.

IM I-e-19

¹H NMR (CDCl₃) delta 8.61 (1 H, br dd, J=4.9, 1.8 Hz), 7.47 (1 H, br dd,J=7.9, 1.8 Hz),7.45 (1H, d, J=1.8 Hz), 7.37 (1H, d, J=7.9 Hz), 7.26 (1H,dd, J=7.9, 1.8 Hz), 7.19 (1 H, br), 7.18 (1H, dd, J=7.9, 4.9 Hz), 6.35(1H, s), 5.31 (1H, s), 4.65 (1 H, dd, J=14.7, 5.5 Hz), 4.60 (1H, dd,J=14.7, 5.5 Hz), 2.86-2.83 (2H, m), 2.46 (1 H, m), 2.26 (1H, m).

MS (ESI) m/z: 365.0 (M+H)⁺.

IM I-e-20

¹H NMR (CDCl₃) delta 8.61 (1H, ddd, J=4.9, 1.8, 1.8 Hz), 7.47 (1H, ddd,J=7.9, 1.8, 1.8 Hz), 7.42 (1H, dd, J=8.6, 6.1 Hz), 7.24-7.13 (3H, m),7.00 (1H, ddd, J=8.6, 3.1, 3.1 Hz), 6.35 (1H, s), 5.31 (1H, s), 4.65(1H, dd, J=15.3, 6.1 Hz), 4.60 (1 H, dd, J=15.3, 6.1 Hz), 2.90-2.79 (2H,m), 2.48 (1H, m), 2.25 (1H, m).

MS (ESI) m/z: 348.9 (M+H)⁺.

IM I-e-21

¹H NMR (CDCl₃) delta 8.60 (1H, dd, J=4.6, 2.0 Hz), 7.48 (1H, dd, J=7.3,2.0 Hz),7.45 (1H, d, J=2.0 Hz), 7.33 (1H, d, J=2.0 Hz), 7.29 (1H, m),7.18 (1H, dd, J=7.3, 4.6 Hz), 6.34 (1H, s), 5.30 (1H, s), 4.79 (1H, dd,J=14.5, 6.6 Hz), 4.60 (1H, m), 4.58 (1H, d, J=11.2 Hz), 4.55 (1H, d,J=11.2 Hz), 3.44 (3 H, s), 2.83 (2H, m), 2.59-2.15 (2H, m).

MS (ESI) m/z: 408.9 (M+H)⁺.

IM I-e-22

MS (ESI) m/z: 367.0 (M+H)⁺.

IM I-e-23

MS (ESI) m/z: 333.1 (M+H)⁺.

IM I-e-24

¹H NMR (CDCl₃) delta 8.68 (1H, ddd, J=4.9, 4.0, 1.8 Hz), 7.61 (1 H, brdt, J=7.9, 1.8 Hz), 7.45 (1H, d, J=1.8 Hz), 7.40-7.35 (1H, m), 7.29-7.15(3H, m), 6.19 (1 H, br d, J=1.8 Hz), 5.35 (1H, br d, J=1.8 Hz), 4.67(1H, dd, J=14.7, 6.1 Hz), 4.59 (1H, dd, J=14.7, 6.1 Hz), 3.58 (1H, m),3.12 (1H, m).

MS (ESI) m/z: 351.1 (M+H)⁺.

IM I-v-1

¹H NMR (CDCl₃) delta 8.44 (1H, m), 7.36 (1H, m), 7.28-7.02 (3H, m), 6.34(0.5 H, br), 5.73 (0.5 H, br), 4.59-4.39 (2H, m), 3.75 (0.5 H, br), 3.66(0.5 H, br t, J=6.6 Hz), 3.40 (0.5 H, m), 3.15 (0.5 H, m), 3.10-2.91(1.5 H, m), 2.73-2.65 (0.5 H, m), 2.50-2.20 (2H, m), 2.55 (1.5 H, s),2.37 (1.5 H, s), 2.07-1.95 (2H, m), 1.44 (4.5 H, s), 1.26 (4.5H, s).

MS (ESI) m/z: 463.1 (M+H)⁺.

IM I-v-2

¹H NMR (CDCl₃) delta 8.47 (1H, m), 7.62 (0.5 H, d, J=8.6 Hz), 7.58 (0.5H, d, J=7.9 Hz), 7.46-7.24 (3H, m), 7.09 (1H, m), 6.88 (0.5 H, br), 5.90(0.5 H, br), 4.68 (0.5 H, dd, J=15.2, 6.6 Hz), 4.59-4.51 (1H, m), 4.39(0.5 H, dd, J=15.8, 5.2 Hz), 3.75 (0.5 H, br d, J=2.6 Hz), 3.72 (0.5 H,br t, J=7.3 Hz), 3.40 (0.5 H, br), 3.28 (0.5 H, dd, J=16.4, 6.0 Hz),3.19 (0.5 H, br), 2.94 (0.5 H, m), 2.68 (0.5 H, dd, J=16.4, 2.6 Hz),2.46 (0.5 H, dd, J=15.8, 9.2 Hz), 2.37-2.30 (0.5 H, m), 2.16-1.97 (3H,m), 1.80-1.67 (0.5 H, m), 1.44 (4.5 H, s), 1.28 (4.5 H, s).

MS (ESI) m/z: 483.0 (M+H)⁺.

IM I-v-3

¹H NMR (CDCl₃) delta 8.55 (1H, m), 7.47 (1H, d, J=7.9 Hz), 7.30 (1H, d,J=2.0 Hz), 7.14 (2H, m), 7.02 (1 H, br), 4.69 (1H, dd, J=13.8, 5.3 Hz),4.61 (1H, dd, J=14.5, 5.3 Hz), 3.45 (1 H, br), 2.92 (1H, dd, J=16.5, 4.6Hz), 2.61-2.48 (1.5 H, m), 2.45 (3 H, s), 2.26-2.05 (2.5 H, m), 1.45 (9H, s).

MS (ESI) m/z: 481.0 (M+H)⁺.

The following Examples and Intermediates were prepared by GeneralProcedure B (Tables 14 and 16).

General Procedure B

The General Procedure B was carried out by the same procedure describedin General Procedure: Scheme 2, Step 5 with/without followingpurification; SCX cartridge column, preparative HPLC to afford thefollowing Examples and Intermediates.

TABLE 14 Examples Structure Chemical Name Substrate 12

N-(2,4-dichloro-6-methylbenzyl)-5-fluoro-8-oxo-5,6,7,8-tetrahydroquinoline- 5-carboxamide

13

N-(2-chloro-3-(trifluoromethyl)benzyl)-5-fluoro-8-oxo-5,6,7,8-tetrahydro- quinoline-5-carboxamide

14

N-(2,4-dichloro-6-(hydroxymethyl)benzyl)-5-fluoro-8-oxo-5,6,7,8-tetrahydro- quinoline-5-carboxamide

15

N-(2,4-dichloro-6-methylbenzyl)-5- hydroxy-8-oxo-5,6,7,8-tetrahydro-quinoline-5-carboxamide

16

N-(2,4-dichloro-6-methylbenzyl)-7-oxo-6,7-dihydro-5H-cyclopenta[b]pyridine- 5-carboxamide

17

N-(2-chloro-3-(trifluoromethyl)benzyl)-7-oxo-6,7-dihydro-5H-cyclopenta[b] pyridine-5-carboxamide

TABLE 15 LC MS Examples Method tR (min) [M + H]⁺ 12 D 1.68 381.0 13 D1.59 401.0 14 A 1.35 397.2 15 A 1.47 379.3 16 D 1.55 349.0 17 D 1.48369.0

Ex 12

¹H NMR (CDCl₃) delta 8.87 (1H, d, J=4.6 Hz), 7.73 (1H, d, J=7.9 Hz),7.52 (1H, dd, J=7.9, 4.6 Hz), 7.33 (1H, d, J=1.3 Hz), 7.16 (1H, d, J=1.3Hz), 7.05 (1H, br d, J=5.9 Hz), 4.71 (1H, dd, J=14.5, 5.9 Hz), 4.64 (1H,dd, J=14.5, 5.9 Hz), 3.17 (1 H, m), 3.00 (1H, m), 2.79 (1H, m), 2.52(1H, m), 2.46 (3 H, s).

Ex 13

¹H NMR (CDCl₃) delta 8.88 (1H, dd, J=4.6, 1.3 Hz), 7.74 (1H, d, J=7.9Hz), 7.71 (1H, d, J=7.9 Hz), 7.63 (1H, d, J=7.9 Hz), 7.51 (1H, dd,J=7.9, 4.6 Hz), 7.40 (1 H, dd, J=7.9, 7.9 Hz), 7.33 (1H, br d, J=5.9Hz), 4.72 (2H, d, J=5.9 Hz), 3.17 (1 H, m), 3.01 (1H, m), 2.59 (1H, m).

Ex 14

¹H NMR (CDCl₃) delta 8.88 (1 H, br dd, J=4.6, 1.3 Hz), 7.69 (1H, d,J=7.9 Hz), 7.59 (1 H, br), 7.50 (1H, dd, J=7.9, 4.6 Hz), 7.45 (1H, d,J=2.0 Hz), 7.34 (1 H, d, J=2.0 Hz), 4.85-4.64 (4H, m), 3.60 (1 H, br),3.18-2.92 (2H, m), 2.76 (1H, m), 2.54 (1H, m).

Ex 15

¹H NMR (DMSO d6) delta 8.70 (1 H, br dd, J=4.6, 2.0 Hz), 8.23 (1 H, br),7.86 (1 H, dd, J=7.9, 2.0 Hz), 7.60 (1H, dd, J=7.9, 4.6 Hz), 7.46 (1H,d, J=2.0 Hz), 7.30 (1H, d, J=2.0 Hz), 6.64 (1 H, s), 4.42 (2H, m),2.89-2.69 (2H, m), 2.43 (1H, m), 2.37 (3 H, s), 2.22 (1H, m).

Ex 16

¹H NMR (DMSO d6) delta 8.82 (1 H, br), 8.77 (1H, d, J=4.6 Hz), 8.00 (1H,d, J=7.9 Hz), 7.63 (1H, dd, J=7.9, 4.6 Hz), 7.50 (1 H, br s), 7.36 (1 H,br s), 4.39 (2 H, br d J=4.6 Hz), 4.29 (1H, m), 2.80 (2H, m), 2.37 (3 H,s).

TABLE 16 Intermediates Structure Chemical Name Substrate I-c-1

N-(2,4-dichlorobenzyl)-8-oxo-5,6,7,8- tetrahydroquinoline-5-carboxamide

I-c-2

N-(2-chloro-4-fluorobenzyl)-8-oxo-5,6,7,8-tetrahydroquinoline-5-carboxamide

I-c-3

N-(2,4-dichloro-6-fluorobenzyl)-8-oxo- 5,6,7,8-tetrahydroquinoline-5-carboxamide

I-c-4

8-oxo-N-(2,3,4-trifluorobenzyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide

I-c-5

8-oxo-N-(2,4,6-trifluorobenzyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide

I-c-6

N-(2,4-difluorobenzyl)-8-oxo-5,6,7,8- tetrahydroquinoline-5-carboxamide

I-c-7

N-(4-fluoro-2-(trifluoromethyl)benzyl)-8-oxo-5,6,7,8-tetrahydroquinoline-5- carboxamide

I-c-8

N-(4-chloro-2-fluorobenzyl)-8-oxo-5,6,7,8-tetrahydroquinoline-5-carboxamide

I-c-9

N-(4-bromo-2-fluorobenzyl)-8-oxo-5,6,7,8-tetrahydroquinoline-5-carboxamide

I-c-10

N-(2-chloro-3,4-difluorobenzyl)-8-oxo- 5,6,7,8-tetrahydroquinoline-5-carboxamide

I-c-11

N-(2-chloro-3-(trifluoromethyl)benzyl)-5-hydroxy-8-oxo-5,6,7,8-tetrahydro- quinoline-5-carboxamide

I-c-12

N-(2,3-dichlorobenzyl)-7-oxo-6,7- dihydro-5H-cyclopenta[b]pyridine-5-carboxamide

IM I-c-1

¹H NMR (CDCl₃) delta 8.60 (1H, dd, J=4.3, 1.8 Hz), 7.67 (1H, dd, J=7.9,1.8 Hz), 7.40 (1H, dd, J=7.9, 4.9 Hz), 7.34 (1H, d, J=1.8 Hz), 7.29 (1H,d, J=7.9 Hz), 7.19 (1H, dd, J=7.9, 1.8 Hz), 6.94 (1H, t, J=5.5 Hz), 4.53(1H, dd, J=14.6, 5.5 Hz), 4.47 (1H, dd, J=14.6, 5.5 Hz), 3.96 (1H, t,J=5.5 Hz), 2.96 (1H, ddd, J=17.7, 10.4, 4.9 Hz), 2.70 (1H, ddd, J=17.7,7.3, 4.9 Hz), 2.53 (1 H, m),2.40 (1 H, m).

MS (ESI) m/z: 349.0 (M+H)⁺.

IM I-c-2

¹H NMR (CDCl₃) delta 8.53 (1H, dd, J=4.3, 1.2 Hz), 7.69 (1H, dd, J=7.9,1.2 Hz), 7.55 (1 H, br), 7.37 (1H, dd, J=7.9, 4.3 Hz), 7.30 (1H, dd,J=8.5, 6.1 Hz), 7.06 (1H, dd, J=8.5, 2.4 Hz), 6.89 (1H, dt, J=8.5, 2.4Hz),4.48 (1H, dd, J=9.8, 5.5 Hz), 4.47 (1H, dd, J=9.8, 5.5 Hz), 4.03(1H, br t, J=5.5 Hz),2.99 (1H, ddd, J=17.7, 9.8, 4.9 Hz), 2.67 (1H, m),2.48 (1H, m), 2.36 (1H, m).

MS (ESI) m/z: 333.1 (M+H)⁺.

IM I-c-3

¹H NMR (CDCl₃) delta 8.52 (1H, m), 7.69 (1H, dd, J=7.9, 1.2 Hz), 7.38 (1H, dd, J=7.9, 4.3 Hz),7.26 (1H, br), 7.16 (1H, d, J=1.8 Hz), 6.97 (1H,dd, J=8.6, 1.8 Hz), 4.59 (1H, dd, J=15.9, 4.9 Hz), 4.55 (1H, dd, J=15.9,4.9 Hz), 3.98 (1 H, br t, J=5.5 Hz), 3.19 (1H, ddd, J=17.7, 10.4, 4.9Hz), 2.66 (1H, m), 2.48 (1H, m), 2.36 (1H, m).

MS (ESI) m/z: 367.0 (M+H)⁺.

IM I-c-4

¹H NMR (CDCl₃) delta 8.53 (1H, dd, J=4.9, 1.2 Hz), 7.99 (1 H, br t,J=5.5 Hz), 7.70 (1H, d, J=7.9 Hz), 7.39 (1H, dd, J=7.9, 4.9 Hz), 7.06(1H, m), 6.89 (1H, m), 4.45 (2H, m), 4.04 (1 H, br t, J=5.5 Hz), 3.03(1H, ddd, J=17.7, 10.4, 4.9 Hz), 2.65 (1H, m), 2.50-2.34 (2H, m).

MS (ESI) m/z: 335.1 (M+H)⁺.

IM I-c-5

¹H NMR (CDCl₃) delta 8.49 (1H, dd, J=4.3, 1.2 Hz), 8.07 (1 H, br t,J=5.5 Hz), 7.69 (1H, d, J=7.9 Hz), 7.39 (1H, dd, J=7.9, 4.3 Hz), 6.62(2H, m), 4.46 (2H, m), 4.01 (1 H, br t, J=5.5 Hz), 2.99 (1H, m), 2.64(1H, m), 2.42-2.28 (2H, m).

MS (ESI) m/z: 335.1 (M+H)⁺.

IM I-c-6

¹H NMR (CDCl₃) delta 8.50 (1H, dd, J=4.9, 1.2 Hz), 7.68 (1H, dd, J=7.9,1.2 Hz), 7.60 (1 H, br t, J=5.5 Hz), 7.36 (1H, dd, J=7.9, 4.9 Hz) 7.26,(1H, ddd, J=15.3, 8.6, 6.7 Hz), 6.80-6.70 (2H, m), 4.45 (1H, dd, J=15.9,5.5 Hz), 4.41 (1 H, dd, J=15.9, 5.5 Hz), 4.02 (1 H, br t, J=5.5 Hz),2.99 (1H, ddd, J=17.7, 10.4, 4.9 Hz), 2.66 (1H, ddd, J=17.7, 7.3, 4.9Hz), 2.50-2.32 (2H, m).

MS (ESI) m/z: 317.1 (M+H)⁺.

IM I-c-7

¹H NMR (CDCl₃) delta 8.55 (1H, dd, J=4.9, 1.2 Hz), 7.66 (1H, dd, J=7.9,1.2 Hz),7.51 (1H, dd, J=8.5, 5.5 Hz), 7.38 (1H, dd, J=7.9, 4.9 Hz), 7.31(1H, dd, J=8.5, 2.4 Hz), 7.18 (1H, ddd, J=8.5, 7.9, 2.4 Hz), 7.12 (1 H,br t, J=6.1 Hz), 4.60 (1 H, dd, J=15.9, 6.1 Hz), 4.55 (1H, dd, J=15.9,6.1 Hz), 3.99 (1 H, br t, J=5.5 Hz), 2.97 (1H, ddd, J=17.7, 9.8, 4.9Hz), 2.68 (1H, ddd, J=17.7, 6.7, 4.9 Hz), 2.53-2.34 (2H, m).

MS (ESI) m/z: 367.1 (M+H)⁺.

IM I-c-8

¹H NMR (CDCl₃) delta 8.49 (1H, dd, J=4.9, 1.2 Hz), 7.67 (1H, dd, J=7.9,1.2 Hz), 7.63 (1 H, br t, J=6.1 Hz), 7.36 (1H, dd, J=7.9, 4.9 Hz), 7.21(1H, dd, J=8.5, 7.3 Hz), 7.02 (1H, dd, J=8.9, 2.4 Hz), 6.99 (1H, dd,J=7.3, 2.4 Hz), 4.43 (1 H, dd, J=15.3, 6.1 Hz), 4.38 (1H, dd, J=15.3,6.1 Hz), 4.00 (1 H, br t, J=5.5 Hz), 2.99 (1H, ddd, J=17.7, 9.8, 4.9Hz), 2.65 (1H, ddd, J=17.7, 6.7, 5.5 Hz), 2.46-2.31 (2H, m).

MS (ESI) m/z: 333.1 (M+H)⁺.

IM I-c-9

¹H NMR (CDCl₃) delta 8.50 (1H, dd, J=4.9, 1.2 Hz), 7.68 (1H, dd, J=7.9,1.2 Hz), 7.60 (1 H, br t, J=6.1 Hz), 7.37 (1H, dd, J=7.9, 4.9 Hz),7.22-7.14 (3H, m), 4.42 (2H, m), 4.00 (1 H, br t, J=5.5 Hz), 2.99 (1H,ddd, J=17.7, 10.4, 4.9 Hz), 2.66 (1H, ddd, J=17.7, 7.3, 4.9 Hz),2.49-2.31 (2H, m).

MS (ESI) m/z: 377.0 (M+H)⁺.

IM I-c-10

¹H NMR (CDCl₃) delta 8.69 (1H, d, J=4.3 Hz), 7.65 (1H, d, J=7.9 Hz),7.44 (1H, dd, J=7.9, 4.3 Hz), 7.15 (1H, m), 7.07 (1H, dd, J=8.6, 7.3Hz), 6.35 (1 H, br), 4.57 (1H, dd, J=15.3, 6.1 Hz), 4.49 (1H, dd,J=15.3, 5.5 Hz), 3.91 (1H, br t, J=5.5 Hz), 2.94 (1H, ddd, J=17.7, 10.4,4.9 Hz), 2.75 (1H, ddd, J=17.7, 6.1, 4.9 Hz), 2.56 (1 H, ddd, J=17.7,11.7, 6.1 Hz), 2.42 (1H, ddd, J=17.7, 10.4, 4.9 Hz).

MS (ESI) m/z: 351.0 (M+H)⁺.

IM I-c-11

¹H NMR (DMSO d6) delta 8.97 (1 H, br t, J=5.9 Hz), 8.71 (1H, d, J=4.6Hz), 7.98 (1H, d, J=7.9 Hz), 7.77 (1H, dd, J=5.9, 2.6 Hz), 7.64 (1H, dd,J=7.9, 4.6 Hz), 7.66-7.50 (2H, m), 6.81 (1 H, s), 4.45 (2 H, br d J=5.9Hz), 2.88-2.70 (2H, m), 2.50 (1H, m), 2.34 (1H, m).

MS (ESI) m/z: 399.3 (M+H)⁺.

IM I-c-12

MS (ESI) m/z: 335.5 (M+H)⁺.

The following Examples and Intermediates were prepared by GeneralProcedure C, D, or E (Tables 17 and 19).

General Procedure C

O₃ was bubbled into a solution of substrate (1.0 eq.) in 50% CH₂Cl₂-MeOHat −78° C. until starting material consumed. N₂ were bubbled into themixture to remove the excess of O₃ at −78° C. The mixture was quenchedwith NaBH₄ (10.0 eq.) and the mixture was warmed to room temperaturegradually. After being stirred at room temperature for 1 h, 10% aq.citric acid was added to the mixture. The mixture extracted with CH₂Cl₂3 times and the extracts were washed with water. The extracts werecombined, dried over Na₂SO₄, and concentrated in vacuo. The resultingresidue was purified by NH gel column chromatography and/or SCXcartridge column, preparative HPLC to afford the following Examples andIntermediates.

General Procedure D

Sodium borohydride (1.5 eq.) was added to a solution of substrate (1.0eq.) in MeOH and the mixture was stirred at room temperature untilcomplete reaction. Water was added to the mixture and the volatile wasremoved by evaporation. The residue was extracted with EtOAc and washedwith brine. The extract was dried over Na₂SO₄ and concentrated in vacuo.The resulting residue was purified by NH gel column chromatographyand/or SCX cartridge column, preparative HPLC to afford the followingExamples and Intermediates.

General Procedure E

To a solution of substrate in CH₂Cl₂ (0.065 M) was added TFA (0.065 M)at room temperature. The mixture was stirred at room temperature untilcomplete reaction, the mixture was poured into water. The mixture wasextracted with CH₂Cl₂. The extract was washed with water, dried overNa₂SO₄ and concentrated in vacuo to afford the following Examples andIntermediates.

TABLE 17 General Examples Structure Chemical Name Substrate Procedure 18

N-(2,4-dichloro-6-methyl- benzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline- 5-carboxamide

D 19

N-(2-chloro-3-(trifluoro- methyl)benzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydro- quinoline-5-carboxamide

D 20

N-(2,4-dichloro-6-(hydroxy methyl)benzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydro quinoline-5-carboxamide

D 21

N-(2,3-dichlorobenzyl)-5- fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5- carboxamide

C 22

N-(2,4-dichlorobenzyl)-5- fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5- carboxamide

C 23

N-(2,4-dichloro-6-(methoxy- methyl)benzyl)-5-fluoro-8hydroxy-5,6,7,8-tetrahydro- quinoline-5-carboxamide

C 24

N-(2,4-dichloro-6-methyl- benzyl)-5,8-dihydroxy-5,6,7,8-tetrahydroquinoline-5- carboxamide

D 25

N-(2-chloro-3-(trifluoro- methyl)benzyl)-5,8- dihydroxy-5,6,7,8-tetrahydroquinoline- 5-carboxamide

D 26

N-(2,4-dichloro-6-methyl- benzyl)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b] pyridine-5-carboxamide

D 27

N-(2-chloro-3-(trifluoro- methyl)benzyl)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b] pyridine- 5-carboxamide

D 28

N-(2,3-dichlorobenzyl)-7- hydroxy-6,7-dihydro-5H-cyclo-penta[b]pyridine-5- carboxamide

D 29

N-(2,4-dichlorobenzyl)-5- fluoro-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridine- 5-carboxamide

C 30

2-(5-((2,4-dichloro-6-methyl- benzyl)carbamoyl)-5,6,7,8-tetrahydroquinolin-8-yl) acetic acid

E 31

2-(5-((2-chloro-3-(trifluoro- methyl)benzyl)carbamoyl)-5,6,7,8-tetrahydroquinolin- 8-yl)acetic acid

E

TABLE 18 LC MS Examples Method tR (min) [M + H]⁺ 18 D 1.66, 1.69 383.019 D 1.56, 1.59 403.0 20 A 1.35 399.2 21 A 1.45 369.1 22 A 1.49 369.1 23A 1.57 413.1 24 A 1.46 381.3 25 A 1.40 401.3 26 D 1.51 351.0 27 D 1.40,1.45 371.0 28 D 1.33, 1.38 337.0 29 D 1.52 355.1 30 A 1.27 407.1 31 A1.23 427.2

Ex 18

¹H NMR (DMSO d6) delta 8.74 (1H, m), 8.60 (1 H, br s), 7.58 (0.4 H, d,J=7.9 Hz), 7.55 (0.6 H, d, J=7.9 Hz), 7.46 (1 H, br s), 7.38 (1H, dd,J=7.9, 4.6 Hz), 7.35 (1 H, br s),5.41 (1H, br s), 4.61 (1H, m),4.48(0.8H, d, J=4.6 Hz),4.43 (1.2H, d, J=4.6 Hz), 2.80-1.75 (4H, m), 2.42(1.2 H, s), 2.38 (1.8 H, s).

Ex 19

¹H NMR (CDCl₃) delta 8.60 (1 H, br), 7.71-7.62 (2H, m), 7.51 (1H, m),7.39 (1H, m), 7.30 (1 H, br), 7.30-7.20 (1H, m), 4.78-4.69 (3H, m), 4.33(0.5 H, br s), 3.75 (0.5 H, br s), 2.76-1.80 (4H, m).

Ex 20

¹H NMR (DMSO d6) delta 8.69 (1 H, br), 8.62 (1 H, br), 7.58 (1H, m),7.56 (1H, d, J=2.6 Hz), 7.48 (1H, d, J=2.6 Hz), 7.38 (1H, dd, J=7.9, 4.6Hz), 5.53 (1 H, br), 5.43 (1H, m), 4.71-4.55 (3H, m), 4.52-4.40 (2H, m),2.40-1.72 (4H, m).

Ex 24

¹H NMR (DMSO d6) delta 8.48 (1 H, br dd, J=4.6, 2.0 Hz), 8.07 (1H, m),7.52-7.45 (2H, m), 7.32 (1 H, J=2.6 Hz), 7.26 (1H, dd, J=7.9, 4.6 Hz),6.23 (0.5 H, s), 6.11 (0.5 H, s), 5.16 (1H, m), 4.54-4.42 (3H, m), 2.41(1.5 H, s), 2.39 (1.5 H, s), 2.30-1.64 (4H, m).

Ex 25

¹H NMR (DMSO d6) delta 8.86 (1H, t, J=6.6 Hz), 8.49 (1H, br d, J=4.6Hz), 7.78 (1H, m), 7.66-7.57 (3H, m), 7.30 (1H, dd, J=7.9, 4.6 Hz), 6.39(0.5 H, br), 6.27 (0.5 H, br), 5.20 (0.5 H, d, J=2.6 Hz), 5.16 (0.5 H,d, J=3.3 Hz), 4.56-4.44 (3H, m), 2.33-1.75 (4H, m).

Ex 26

¹H NMR (DMSO d6) delta 8.53 (1 H, br), 8.44 (1H, d, J=4.6 Hz), 7.52 (1H,d, J=7.9 Hz), 7.50 (1H, d, J=2.0 Hz), 7.36 (1H, d, J=2.0 Hz), 7.23 (1H,dd, J=7.9, 4.6 Hz),5.48 (1H, d, J=6.6 Hz), 4.90 (1H, m), 4.44 (1H, d,J=4.6 Hz), 4.42 (1H, d, J=4.6 Hz), 3.82 (1H, m), 2.54 (1H, m), 2.39 (3H, s), 2.02 (1H, m).

Ex 29

¹H NMR (CDCl₃) delta 8.69 (1 H, br dd, J=4.9, 1.2 Hz), 7.62 (1 H, br dd,J=7.9, 1.2 Hz), 7.44 (1H, d, J=1.8 Hz), 7.35-7.16 (4H, m), 5.33 (1H, dd,J=6.1, 2.4 Hz), 4.63 (1H, dd, J=14.7, 6.1 Hz), 4.57 (1H, dd, J=14.7, 6.1Hz), 3.94 (1H, d, J=5.5 Hz), 2.83-2.66 (2H, m).

TABLE 19 Procedure Intermediate Structure Chemical Name SubstrateGeneral I-w-1

2-(5-((2,4-dichloro-6- methylbenzyl)carbamoyl)- 5-fluoro-5,6,7,8-tetra-hydroquinolin-8-yl)acetic acid

E

IM I-w-1

MS (ESI) m/z: 425.0 (M+H)⁺.

The following Example was prepared by General Procedure A (Table 20).

TABLE 20 Example Structure Chemical Name Substrate Amine 32

(2-amino-2-oxoethyl)-N- (2-chloro-3-(trifluoro-methyl)benzyl)-5,6,7,8-tetra- hydroquinoline-5- carboxamide

NH₄Cl

Ex 32

LCMS (ESI) m/z: 426.2 (M+H)⁺, tR 1.39 min (Method A).

The following Examples were prepared by General Procedure F (Table 21).

General Procedure F

A mixture of substrate (1.0 eq.), 4% aq. OsO₄ (1.0 eq.), and NMO (15.0eq.) in 50% aq. THF was stirred at room temperature until completereaction. Aq. Na₂S₂O₃ was added to the mixture and the mixture wasstirred for 10 min. The mixture was extracted with EtOAc twice. Theextracts were washed with brine, dried over Na₂SO₄, and concentrated invacuo. The resulting residue was purified by silica gel columnchromatography and/or SCX column, preparative HPLC to afford thefollowing Examples.

TABLE 21 Examples Structure Chemical Name Substrate 33

N-(2,4-dichloro-6-methylbenzyl)-8-hy-droxy-8-(hydroxymethyl)-5,6,7,8-tetra- hydroxuqinoline-5-carboxamide

34

N-(2,4-dichloro-6-methylbenzyl)-5- fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5- carboxamide

35

N-(2-chloro-3-(trifluoromethyl)benzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)- 5,6,7,8-tetrahydroquinoline-5-carboxamide

36

N-(2,3-dichlorobenzyl)-5-fluoro-8-hy-droxy-8-(hydroxymethyl)-5,6,7,8-tetra- hydroquinoline-5-carboxamide

37

N-(2,4-dichlorobenzyl)-5-fluoro-8-hy-droxy-8-(hydroxymethyl)-5,6,7,8-tetra- hydroquinoline-5-carboxamide

38

N-(2,4-dichlorobenzyl)-5-fluoro-7-hydroxy-7-(hydroxymethyl)-6,7-dihydro- 5H-cyclopenta[b]pyridine-5-carboxamide

TABLE 22 LC MS Examples Method tR (min) [M + H]⁺ 33 A 1.41 395.3 34 A1.52 413.1 35 A 1.44 433.1 36 A 1.39 399.1 37 A 1.42 399.1 38 D 1.41385.1

The following Intermediates were prepared by General Procedure G or H(Table 23).

General Procedure G

A substrate (1.0 eq.) and trimethylsulfoxonium iodide (1.2 eq.) weredissolved in DMSO. A solution of KOBu^(t) (1.2 eq.) in DMSO was added tothe mixture at ambient temperature. After being stirred at roomtemperature until complete reaction, the mixture was poured intoice-water. The mixture was extracted with EtOAc twice and washed withbrine. The extracts were combined, dried over Na₂SO₄, and concrete invacuo. The resulting residue was purified by silica gel columnchromatography to afford the following Intermediates. The each diasteroisomer can be separated by silica gel column chromatography.

General Procedure H

To a solution of substrate (1.0 eq.) in water-tert-BuOH-THF (2:1:1) wasadded NBS (2.0 eq.) in portions at ambient temperature and then themixture was heated at 50° C. until starting material consumed. Aftercooling to 0° C., the reaction mixture was basified with 5 M aqueousNaOH and stirred at 0° C. until complete reaction. The reaction mixturewas poured into water and extract with EtOAc twice. The extracts werewashed with brine, and dried over Na₂SO₄. The combined extracts wereevaporated and the resulting residue was purified by silica gel columnchromatography to afford the following Intermediates. The each diastereoisomer can be separated by silica gel column chromatography.

TABLE 23 General Intermediates Structure Chemical Name SubstrateProcedure I-g-1

N-(2,4-dichloro-6-meth- ylbenzyl)-6′,7′-dihydro- 5′H-spiro[oxirane-2,8′-quinoline]-5′- carboxamide

G I-g-2

N-(2,4-dichloro-6-meth- ylbenzyl)-5′-fluoro-6′,7′-dihydro-5′H-spiro[oxirane- 2,8′-quinoline]-5′- carboxamide

G I-g-3

N-(2-chloro-3-(trifluoro- methyl)benzyl)-5′-fluoro-6′,7′-dihydro-5′H-spiro [oxirane-2,8′-quinoline]- 5′-carboxamide

G I-g-4

(2S*,5′S*)-N-(2,4-dichloro- benzyl)-5′-fluoro-6′,7′-dihydro-5′H-spiro[oxirane- 2,8′-quinoline]-5′- carboxamide

H I-g-5

(2R*,5′S*)-N-(2,4-dichloro- benzyl)-5′-fluoro-6′,7′-dihydro-5′H-spiro[oxirane- 2,8′-quinoline]-5′- carboxamide I-g-6

(2S*,5′S*)-N-(2-chloro- 4-fluorobenzyl)-5′-fluoro-6′,7′-dihydro-5′H-spiro [oxirane-2,8′-quinoline]- 5′-carboxamide

H I-g-7

(2R*,5′S*)-N-(2-chloro- 4-fluorobenzyl)-5′-fluoro-6′,7′-dihydro-5′H-spiro [oxirane-2,8′-quinoline]- 5′-carboxamide

IM I-g-1

¹H NMR (CDCl₃) delta 8.53 (1H, dd, J=4.6, 1.3 Hz), 7.45 (0.5 H, d, J=7.9Hz), 7.42 (0.5H, dd, J=7.9, 1.3 Hz),7.24 (0.5H, d, J=2.0 Hz),7.22 (0.5H,d, J=2.0 Hz),7.18 (1H, dd, J=7.9, 4.6 Hz), 7.11 (0.5H, d, J=2.0 Hz),7.10(0.5H, d, J=2.0 Hz), 5.94 (0.5 H, br t, J=5.9 Hz), 5.79 (0.5 H, br t,J=5.9 Hz), 4.63-4.41 (2H, m), 3.75 (1H, m), 3.73 (0.5 H, d, J=5.9 Hz),3.62 (0.5 H, d, J=5.9 Hz), 2.98 (0.5 H, d, J=5.9 Hz), 2.97 (0.5 H, d,J=5.9 Hz), 2.47 (1.5 H, s), 2.46 (1.5 H, s), 2.50-1.80 (4H, m).

MS (ESI) m/z: 377.0 (M+H)⁺.

IM I-g-2

MS (ESI) m/z: 395.0 (M+H)⁺.

IM I-g-3

¹H NMR (CDCl₃) delta 8.63 (1H, dd, J=4.6, 2.0 Hz), 7.67 (2H, m), 7.44(2H, m), 7.30-7.04 (2H, m), 4.75 (2H, d, J=5.9 Hz), 3.86 (1H, d, J=5.9Hz), 3.03 (1 H, d, J=5.9 Hz), 2.99-2.00 (4H, m).

MS (ESI) m/z: 414.9 (M+H)⁺.

IM I-g-4

¹H NMR (CDCl₃) delta 8.63 (1 H, br dd, J=4.9, 1.8 Hz), 7.50 (1 H, br dd,J=7.9, 1.8 Hz),7.46 (1H, d, J=2.4 Hz), 7.39 (1H, d, J=8.6 Hz), 7.27 (1H,br dd, J=7.9, 1.8 Hz), 7.23 (1H, dd, J=7.9, 4.9 Hz), 7.19 (1 H, br),4.67 (1H, dd, J=14.7, 6.1 Hz), 4.62 (1H, dd, J=14.7, 6.1 Hz), 3.86 (1H,d, J=6.1 Hz), 3.03 (1H, d, J=6.1 Hz), 2.76 (1H, m), 2.57 (1H, m), 2.32(1H, m), 2.14 (1H, m).

MS (ESI) m/z: 380.9 (M+H)⁺.

IM I-g-5

¹H NMR (CDCl₃) delta 8.63 (1H, ddd, J=4.9, 1.8, 1.2 Hz), 7.51 (1H, ddd,J=7.9, 1.8, 1.2 Hz),7.46 (1H, d, J=1.8 Hz), 7.37 (1H, d, J=7.9 Hz), 7.27(1H, dd, J=7.9, 1.8 Hz), 7.24 (1 H, br), 7.22 (1H, dd, J=7.9, 4.9 Hz),4.65 (1H, dd, J=14.7, 6.1 Hz), 4.60 (1H, dd, J=14.7, 6.1 Hz), 3.51 (1H,d, J=6.1 Hz), 3.06 (1H, d, J=6.1 Hz), 2.65 (1H, m), 2.50-2.39 (2H, m),2.19 (1H, m).

MS (ESI) m/z: 380.9 (M+H)⁺.

IM I-g-6

¹H NMR (CDCl₃) delta 8.63 (1H, ddd, J=4.9, 1.8, 1.2 Hz), 7.49 (1H, ddd,J=7.9, 1.8, 1.2 Hz), 7.44 (1H, dd, J=8.6, 5.5 Hz), 7.23 (1H, dd, J=7.9,4.9 Hz), 7.18 (1H, dd, J=8.6, 2.4 Hz), 7.17 (1 H, br), 7.01 (1H, ddd,J=8.6, 7.9, 2.4 Hz), 4.67 (1H, dd, J=14.7, 6.1 Hz), 4.62 (1H, dd,J=14.7, 6.1 Hz), 3.86 (1H, d, J=6.1 Hz), 3.03 (1H, d, J=6.1 Hz), 2.77(1H, m), 2.57 (1H, m), 2.32 (1H, m), 2.13 (1H, m).

MS (ESI) m/z: 365.1 (M+H)⁺.

IM I-g-7

¹H NMR (CDCl₃) delta 8.62 (1 H, br dd, J=4.9, 1.8 Hz), 7.51 (1 H, br dd,J=7.9, 1.8 Hz), 7.42 (1H, dd, J=8.5, 6.1 Hz), 7.23-7.18 (3H, m), 7.00(1H, m), 4.66 (1H, dd, J=14.7, 6.1 Hz), 4.60 (1H, dd, J=14.7, 6.1 Hz),3.51 (1H, d, J=6.1 Hz), 3.06 (1 H, d, J=6.1 Hz), 2.66 (1H, m), 2.51-2.39(2H, m), 2.19 (1H, m).

MS (ESI) m/z: 364.7 (M+H).

The following Examples were prepared by General Procedure I, J, or K(Table 24).

General Procedure I

A solution of 1.0 M NaOMe in MeOH (1.3 eq.) was added to substrate (1.0eq.) in small portions at ambient temperature. After being stirred atroom temperature until complete reaction, the mixture was concentratedin vacuo to afford a glass. The residual glass was distributed betweenEtOAc and water. The extract was dried over Na₂SO₄ and concentrated invacuo. The resulting residue was purified by SCX cartridge column andpreparative HPLC to afford the following Examples.

General Procedure J

A solution of substrate (1.0 eq.) in MeOH was treated with amine (45eq.) at room temperature until complete reaction. The mixture wasconcentrated in vacuo and the resulting residue was distributed betweenEtOAc and water. The extract was dried over Na₂SO₄ and concentrated invacuo. The resulting residue was purified by silica gel columnchromatography and/or SCX column and preparative HPLC to afford thefollowing Examples.

General Procedure K

To a stirred solution of substrate (1.0 eq.) in EtOH was added NaBH₄(6.0 eq.) at ambient temperature. The mixture was stirred at roomtemperature until complete reaction, water was added to the mixture. Themixture was extracted with EtOAc and washed with aq. NaHCO₃. The extractwas dried over Na₂SO₄ and concentrated in vacuo. The resulting residuewas purified by SCX cartridge column and preparative HPLC to afford thefollowing Examples.

TABLE 24 Ex- General am- Procedure ples Structure Chemical NameSubstrate (/Amine) 39

N-(2,4-dichloro-6- methylbenzyl)-5- fluoro-8-hydroxy-8- (methoxymethyl)-5,6,7,8-tetrahydro- quinoline-5- carboxamide

I 40

N-(2-chloro-3-(tri- fluoromethyl)benzyl)- 5-fluoro-8-hydroxy-8-(methoxy- methyl)-5,6,7,8-tetra- hydroquinoline-5- carboxamide

I 41

(5S*,8S*)-N-(2,4- dichlorobenzyl)- 5-fluoro-8-hydroxy-8-(methoxymethyl)- 5,6,7,8-tetrahydro- quinoline-5- carboxamide

I 42

(5S*,8S*)-N-(2- chloro-4-fluoro- benzyl)-5-fluoro- 8-hydroxy-8-(methoxymethyl)- 5,6,7,8-tetra- hydroquinoline-5- carboxamide

I 43

8-(aminomethyl)-N- (2,4-dichloro-6-meth- ylbenzyl)-8- hydroxy-5,6,7,8-tetrahydroquinoline- 5-carboxamide

J/ NH₄OH 44

N-(2,4-dichloro-6- methylbenzyl)-8- hydroxy-8-((methyl- amino)methyl)-5,6,7,8-tetrahydro- quinoline-5- carboxamide J/ MeNH₂ in MeOH 45

8-(aminomethyl)- N-(2,4-dichloro-6- methylbenzyl)-5- fluoro-8-hydroxy-5,6,7,8-tetrahydro- quinoline-5- carboxamide J/ NH₄OH 46

N-(2,4-dichloro-6- methylbenzyl)- 5-fluoro-8- hydroxy-8-((methyl- amino)methyl)-5,6,7,8-tetra- hydroquinoline-5- carboxamide J/ MeNH₂ in MeOH 47

N-(2,4-dichloro- 6-meth- ylbenzyl)-8-((dimeth- ylamino)meth-yl)-5-fluoro-8- hydroxy-5,6,7,8- tetrahydroquinoline- 5-carboxamide J/Me₂NH in THF 48

8-(aminomethyl)-N- (2-chloro-3-(trifluoro- methyl)benzyl)-5-fluoro-8-hy- droxy-5,6,7,8-tetra- hydroquinoline- 5-carboxamide

J/ NH₄OH 49

N-(2-chloro-3- (trifluorometh- yl)benzyl)-5-fluoro- 8-hydroxy-8-((methylamino)meth- yl)-5,6,7,8- tetrahydroquinoline- 5-carboxamide J/MeNH₂ in MeOH 50

N-(2-chloro-3- (trifluoro- methyl)benzyl)-8-((di- methylamino)methyl)-5-fluoro-8-hydroxy- 5,6,7,8- tetrahydroquinoline- 5-carboxamide J/ Me₂NHin THF 51

(5S*,8R*)-N- (2,4-dichlorobenzyl)- 5-fluoro-8-hydroxy- 8-((3-hydroxyaze-tidin-1-yl)methyl)- 5,6,7,8-tetrahydro- quinoline-5- carboxamide

52

(5S*,8R*)-N-(2-chloro- 4-fluorobenzyl)- 5-fluoro-8-hy-droxy-8-((3-hydroxy- azetidin-1-yl)methyl)- 5,6,7,8-tetrahydro-quinoline-5- carboxamide

53

(5S*,8R*)-N-(2-chloro- 4-fluorobenzyl)- 5-fluoro-8-hydroxy-8-((3-methoxy- azetidin-1-yl)methyl)- 5,6,7,8-tetrahydro- quinoline-5-carboxamide

54

(5S*,8R*)-N-(2-chloro- 4-fluorobenzyl)- 5-fluoro-8-hydroxy-8-((3-hydroxy- 3-methylazetidin-1-yl) methyl)-5,6,7,8-tetra-hydroquinoline-5- carboxamide

55

(5S*,8R*)-N-(2-chloro- 4-fluorobenzyl)-5- fluoro-8-hydroxy-8-((3-methoxy- 3-methylazetidin-1-yl) methyl)-5,6,7,8-tetra-hydroquinoline-5- carboxamide

56

(5S*,8R*)-N-(2-chloro- 4-fluorobenzyl)-5- fluoro-8-hydroxy-8-(((2-hydroxy- ethyl)amino)methyl)- 5,6,7,8-tetrahydro- quinoline-5-carboxamide

57

(5S*,8R*)-N-(2- chloro-4- fluorobenzyl)-5-fluoro- 8-hydroxy-8-(((2-hydroxyethyl)(meth- yl)amino) methyl)-5,6,7,8- tetrahydroquinoline-5-carboxamide

58

N-(2-chloro- 3-(trifluoro- methyl)benzyl)- 5-fluoro- 8-hydroxy-8-methyl-5,6,7,8-tetrahydro- quinoline-5- carboxamide

K

TABLE 25 LC MS Examples Method tR (min) [M + H]⁺ 39 A 1.67 427.1 40 A1.57 447.1 43 A 1.35 394.2 44 A 1.36 408.1 45 A 1.42 412.2 46 A 1.45426.2 47 A 1.50 440.2 48 A 1.36 432.1 49 A 1.38 446.1 50 A 1.43 460.1 58A 1.58 417.1

Ex 41

¹H NMR (DMSO d6) delta 9.27 (1 H, br s), 8.74 (1H, d, J=4.5 Hz),7.75-7.80 (2H, m), 7.62 (1H, d, J=2.0 Hz), 7.53 (1H, dd, J=8.0, 4.7 Hz),7.45 (1H, dd, J=8.4, 2.1 Hz), 7.36 (1H, d, J=8.3 Hz), 4.40 (2H, t, J=5.3Hz), 3.88 (1H, d, J=8.6 Hz), 3.53 (1H, d, J=8.4 Hz) 2.29-2.48 (5H, m).

MS (ESI) m/z: 413.2 (M+H)⁺.

Ex 42

¹H NMR (CDCl₃) delta 8.61 (1 H, dt, J=4.7, 1.6 Hz), 7.51 (1 H, dt,J=7.8, 1.5 Hz), 7.40 (1H, dd, J=8.5, 6.1 Hz), 7.14-7.25 (3H, m), 6.99 (1H, td, J=8.3, 2.6 Hz), 4.51-4.68 (2H, m), 3.76 (2H, dd, J=9.5, 8.4 Hz),3.34-3.37 (4H, m), 2.57-2.72 (1 H, m), 2.38-2.49 (1H, m) 2.18-2.32 (2H,m).

MS (ESI) m/z: 397.2 (M+H)⁺.

Ex 51

¹H NMR (CDCl₃) delta 8.61 (1H, br d, J=4.7 Hz), 7.54 (1H, d, J=8.0 Hz),7.44 (1 H, d, J=2.1 Hz), 7.34 (1H, d, J=7.7 Hz), 7.27-7.30 (1H, m),7.19-7.25 (1H, m), 4.48-4.65 (3H, m), 3.99-4.13 (4H, m), 3.89 (2 H, brs), 3.56 (1H, br d, J=13.0 Hz), 3.18 (1H, br d, J=13.1 Hz), 2.67-2.82(1H, m), 2.16-2.28 (3H, m).

MS (ESI) m/z: 454.2 (M+H)⁺. Ex 52

¹H NMR (CDCl₃) delta 8.62 (1 H, dt, J=4.7, 1.6 Hz), 7.49 (1 H, dt,J=7.8, 1.5 Hz), 7.41 (1H, dd, J=8.5, 6.1 Hz), 7.09-7.25 (3H, m), 6.99 (1H, td, J=8.3, 2.6 Hz), 4.53-4.67 (2H, m), 4.41 (1 H, quin, J=5.78 Hz),3.74-3.82 (1H, m), 3.57 (1 H, br s), 3.07-3.16 (2H, m), 3.00 (1 H, br t,J=6.4 Hz), 2.85 (1H, d, J=12.8 Hz), 2.56-2.77 (1 H, m), 2.13-2.37 (4H,m).

MS (ESI) m/z: 438.3 (M+H)⁺.

Ex 53

¹H NMR (CDCl₃) delta 8.61-8.64 (1H, m), 7.49 (1H, d, J=7.6 Hz), 7.41 (1H, dd, J=8.6, 6.0 Hz), 7.09-7.25 (3H, m), 6.99 (1 H, td, J=8.3, 2.6 Hz),4.54-4.66 (2H, m), 4.03 (1 H, br t, J=5.8 Hz), 3.66-3.84 (1H, m), 3.58(1 H, br s), 3.15-3.24 (4H, m), 2.95-3.10 (1H, m), 2.85 (1H, br d,J=12.8 Hz), 2.58-2.72 (1H, m), 2.08-2.35 (3H, m).

MS (ESI) m/z: 452.0 (M+H)⁺.

Ex 54

¹H NMR (CDCl₃) delta 8.62 (1H, d, J=5.0 Hz), 7.50 (1H, d, J=7.6 Hz),7.41 (1H, dd, J=8.6, 6.0 Hz), 7.10-7.25 (3H, m), 6.99 (1 H, td, J=8.3,2.6 Hz), 4.54-4.67 (2H, m), 3.46 (1H, d, J=8.0 Hz), 3.22-3.39 (4H, m),2.90 (1H, d, J=12.8 Hz), 2.59-2.74 (1H, m), 2.14-2.27 (3H, m), 1.45 (3H, s).

MS (ESI) m/z: 452.3 (M+H)⁺.

Ex 55

¹H-NMR (CDCl₃) delta 8.62 (1 H, dt, J=4.7, 1.6 Hz), 7.48 (1H, d, J=7.6Hz), 7.41 (1H, t, J=7.0 Hz), 7.08-7.24 (3H, m), 6.99 (1 H, td, J=8.3,2.6 Hz), 4.53-4.67 (2H, m), 3.14-3.41 (6H, m), 3.10 (2 H, br s), 2.83(1H, br d, J=12.6 Hz), 2.49-2.76 (1H, m), 2.13-2.37 (3H, m), 1.43 (3 H,s).

MS (ESI) m/z: 466.3 (M+H)⁺.

Ex 56

¹H-NMR (CDCl₃) delta 8.59 (1 H, dt, J=4.7, 1.7 Hz), 7.50 (1 H, dt,J=7.9, 1.5 Hz), 7.41 (1H, dd, J=8.4, 6.0 Hz), 7.13-7.25 (3H, m), 6.99 (1H, td, J=8.3, 2.6 Hz), 4.55-4.67 (2H, m), 3.64 (2H, t, J=5.2 Hz), 3.12(1H, d, J=12.0 Hz), 2.92 (1 H, d, J=12.0 Hz), 2.68-2.83 (2H, m),2.28-2.36 (1H, m), 2.13-2.25 (3H, m).

MS (ESI) m/z: 426.3 (M+H)⁺.

Ex 57

¹H-NMR (CDCl₃) delta 8.62 (1 H, dt, J=4.7, 1.7 Hz), 7.51 (1H, d, J=7.6Hz), 7.41 (1H, dd, J=8.5, 6.1 Hz), 7.10-7.25 (3H, m), 6.99 (1 H, td,J=8.3, 2.6 Hz), 4.54-4.67 (2H, m), 3.43-3.66 (3H, m), 3.03 (1H, d,J=14.1 Hz), 2.87 (1H, br d, J=14.2 Hz), 2.57-2.73 (3H, m), 2.14-2.41(6H, m).

MS (ESI) m/z: 440.0 (M+H)⁺.

The following Intermediates were prepared by General Procedure L (Table26).

General Procedure L

NaN₃ (3.0 eq.) and NH₄Cl (3.0 eq.) were added to a solution of substrate(1.0 eq.) in MeOH, and the mixture was stirred at 60° C. until completereaction. The reaction was quenched with aq. NaHCO₃, and the resultingmixture was extracted with CHCl₃. The extract was concentrated underreduced pressure to afford the following Intermediates.

TABLE 26 Intermediates Structure Chemical Name Substrate I-h-3-1

(5S*,8R*)-8-(azidomethyl)-N-(2,4- dichlorobenzyl)-5-fluoro-8-hy-droxy-5,6,7,8-tetrahydro- quinoline-5-carboxamide

I-h-3-2

(5S*,8S*)-8-(azidomethyl)-N-(2,4- dichlorobenzyl)-5-fluoro-8-hy-droxy-5,6,7,8-tetrahydro- quinoline-5-carboxamide

IM I-h-3-1

¹H-NMR (CDCl₃) delta 8.65 (1 H, dt, J=4.7, 1.71 Hz), 7.53 (1 H, dt,J=7.9, 1.5 Hz), 7.45 (1H, d, J=2.1 Hz), 7.36 (1H, d, J=8.2 Hz),7.27-7.31 (2H, m), 7.16 (1H, br d, J=5.3 Hz), 4.54-4.67 (2H, m), 3.70(2H, d, J=1.1 Hz), 3.20 (s, 1H), 2.59-2.74 (1H, m), 2.36-2.46 (1H, m),2.13-2.33 (2H, m).

MS (ESI) m/z: 424.2 (M+H)⁺.

IM I-h-3-2

¹H-NMR (CDCl₃) delta 8.60-8.66 (1H, m), 7.52 (1H, d, J=8.2 Hz), 7.46 (1H, s), 7.17-7.39 (6H, m), 4.54-4.68 (2H, m), 3.53-3.60 (1H, m), 3.41(1H, d, J=13.0 Hz), 2.41-2.55 (2H, m), 2.26-2.39 (1H, m), 2.01-2.21 (1H,m).

MS (ESI) m/z: 424.2 (M+H)⁺.

General Procedure: Scheme 11, Step 1

To a stirred solution of substrate (1.0 eq.) in MeCN and water (100 eq.)at 60° C. was added portion wise triphenyl phosphine (2.0 eq.). Themixture was stirred at that temperature until complete reaction. Themixture was purified by silica gel column chromatography to afford thefollowing Intermediates (Table 27).

TABLE 27 Intermediates Structure Chemical Name Substrate I-m-1

(2S*,5′S*)-N-(2,4-dichloro- benzyl)-5′-fluoro- 6′,7′-dihydro-5′H-spiro[azidine-2,8′-quinoline]- 5′-carboxamide

I-m-2

(2R*,5′S*)-N-(2,4-dichloro- benzyl)-5′- fluoro-6′,7′-dihydro-5′H-spiro[aziridine-2,8′-quinoline]- 5′-carboxamide

IM I-m-1

¹H-NMR (CDCl₃) delta 8.46 (1 H, dt, J=4.7, 1.9 Hz), 7.21-7.48 (6H, m),7.13 (1H, ddd, J=7.8, 4.8, 0.9 Hz), 4.57-4.72 (2H, m), 2.57-2.78 (1H,m), 2.45-2.55 (1H, m), 2.34 (1H, tdd, J=14.1, 14.1, 4.3, 2.9 Hz),2.16(1H, s) 1.91 (1H, s), 1.71 (1H, dt, J=13.6, 3.7 Hz).

MS (ESI) m/z: 380.1 (M+H)⁺.

IM I-m-2

¹H-NMR (CDCl₃) delta 8.47 (1 H, dt, J=4.7, 1.7 Hz), 7.63-7.70 (1H, m),7.32-7.49 (4H, m), 7.19-7.29 (2H, m), 7.13 (1H, ddd, J=7.9, 4.7, 0.7Hz), 4.54-4.68 (2H, m), 2.49-2.70 (3H, m), 2.23-2.36 (2H, m), 2.09-2.20(1H, m).

MS (ESI) m/z: 380.1 (M+H)⁺.

General Procedure: Scheme 11, Step 2

Triethylamine (1.5 eq.) and 2-nitrophenylsulfonyl chloride (1.2 eq.)were successively added to a dichloromethane solution of substrate (1.0eq.) at 0° C. After stirring at ambient temperature until completereaction, the reaction was quenched with aq. NH₄Cl. The mixture wasextracted with CHCl₃, dried over Na₂SO₄, and concentrated under reducedpressure to afford the following Intermediates (Table 28).

TABLE 28 Intermediates Structure Chemical Name Substrate XIV-1

(2S*,5′S*)-N-(2,4-dichlorobenzyl)-5′-fluoro-1-((2-nitrophenyl)sulfonyl)-6′,7′-dihydro-5′H-spiro[aziridine- 2,8′-quinoline]-5′-carboxamide

XIV-2

(2R*,5′S*)-N-(2,4-dichlorobenzyl)-5′-fluoro-1-((2-nitrophenyl)sulfonyl)-6′,7′-dihydro-5′H-spiro[aziridine- 2,8′-quinoline]-5′-carboxamide

IM XIV-1

MS (ESI) m/z: 565.0 (M+H)+

IM XIV-2

MS (ESI) m/z: 565.0 (M+H)⁺.

General Procedure: Scheme 11, Step 3

To a solution of substrate (1.0 eq.) in DMF was added NaOAc (10 eq.) andthe mixture was stirred at 100° C. until starting material consumed. Aq.NaOH (5 N, 5 eq.) was added to the mixture and stirred at ambienttemperature until complete reaction. The reaction was quenched with aq.NH₄Cl, extracted with CHCl₃. The extract was concentrated under reducedpressure. The residue was purified by silica gel column chromatographyto afford the following Intermediates (Table 29).

TABLE 29 Intermediates Structure Chemical Name Substrate XV-1

(5S*,8R*)-N-(2,4-dichlorobenzyl)- 5-fluoro-8-(hydroxymethyl)-8-(2-nitro-phenylsulfonamido)-5,6,7,8-tetra- hydroquinoline-5-carboxamide

XV-2

(5S*,8S*)-N-(2,4-dichlorobenzyl)-5- fluoro-8-(hydroxymethyl)-8-(2-nitro-phenylsulfonamido)-5,6,7,8-tetra- hydroquinoline-5-carboxamide

IM XVI-1

MS (ESI) m/z: 583.1 (M+H)⁺.

IM XV-2

MS (ESI) m/z: 583.1 (M+H)⁺.

General Procedure: Scheme 11, Step 4

The mixture of substrate (1.0 eq.), 4-mercaptobenzoic acid (2.0 eq.),and K₂CO₃ (4.0 eq.) in DMF was stirred at 80° C. until completereaction. The solvent of the mixture was removed under reduced pressure.The residue was purified by SCX cartridge column to afford the followingExamples (Table 30).

TABLE 30 Examples Structure Chemical Name Substrate 59

(5S*,8R*)-8-amino-N-(2,4-dichloro- benzyl)-5-fluoro-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5- carboxamide

60

(5S*,8S*)-8-amino-N-(2,4-dichloro- benzyl)-5-fluoro-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5- carboxamide

Ex 59

¹H-NMR (CDCl₃) delta 8.56-8.65 (1H, m), 7.50 (1H, br d, J=8.1 Hz), 7.45(1H, d, J=2.2 Hz), 7.30-7.39 (1H, m), 7.13-7.29 (3H, m), 4.60 (2H, dd,J=10.0, 5.9 Hz), 2.90-3.09 (2H, m), 2.29-2.45 (2H, m), 2.05-2.17 (2H,m).

MS (ESI) m/z: 398.2 (M+H)⁺.

EX 60

¹H-NMR (CDCl₃) delta 8.54 (1H, dd, J=2.7, 1.3 Hz), 7.52 (1H, d, J=7.3Hz) 7.40-7.44 (1H, m), 7.27-7.36 (2H, m), 7.12-7.25 (3H, m), 4.51-4.65(2H, m), 3.14-3.31 (2H, m), 2.67-3.00 (2H, m), 2.17-2.31 (2H, m).

MS (ESI) m/z: 398.2 (M+H)⁺.

General Procedure: Scheme 12, Step 1

Chloroacetyl chloride (1.1 eq.) was added dropwise to a biphasicsolution of substrate (1.0 eq.) in dichloromethane (0.3 M) and 0.5 N aq.NaOH (2.0 eq) at 0° C. The reaction mixture was warmed up to ambienttemperature and stirred at that temperature until complete reaction. Themixture was extracted with dichloromethane 3 times, dried over Na₂SO₄,and concentrated under reduced pressure to afford the followingIntermediates (Table 31).

TABLE 31 Intermediates Structure Chemical Name Substrate XVI-1

(5S*,8R*)-8-(2-chloroacetamido)- N-(2,4-dichlorobenzyl)-5-fluoro-8-(hydroxymethyl)-5,6,7,8-tetrahydro- quinoline-5-carboxamide

XVI-2

(5S*,8S*)-8-(2-chloroacetamido)- N-(2,4-dichlorobenzyl)-5-fluoro-8-(hydroxymethyl)-5,6,7,8-tetrahydro- quinoline-5-carboxamide

IM XVI-1

MS (ESI) m/z: 474.1 (M+H)⁺.

IM XVI-2

MS (ESI) m/z: 474.1 (M+H)⁺.

General Procedure: Scheme 12, Step 2

To a solution of substrate (1.0 eq.) in 50% dichloromethane/2-propanolwas added portion wise tert-BuOK (4.0 eq.) at 0° C. The solution wasallowed to warm to ambient temperature and stirred until completereaction. The solvent was removed under reduced pressure and theresulting crude residue was purified by preparative HPLC to afford thefollowing Examples (Table 32).

TABLE 32 Examples Structure Chemical Name Substrate 61

(3R*,5′S*)-N-(2,4-dichlorobenzyl)- 5′-fluoro-5-oxo-6′,7′-dihydro-5′H-spiro[morpholine-3,8′-quinoline]- 5′-carboxamide

62

(3S*,5′S*)-N-(2,4-dichlorobenzyl)- 5′-fluoro-5-oxo-6′,7′-dihydro-5′H-spiro[morpholine-3,8′-quinoline]- 5′-carboxamide

Ex 61

¹H-NMR (CDCl₃) delta 8.61-8.69 (1H, m), 7.54 (1H, d, J=7.7 Hz), 7.46 (1H, d, J=2.0 Hz), 7.16-7.40 (6H, m), 6.18 (1 H, br s), 4.56-4.69 (2H, m),4.34 (1H, dd, J=12.2, 2.2 Hz), 4.17 (2H, dd, J=17.5, 16.6 Hz), 3.37 (1H,dd, J=12.2, 2.9 Hz), 2.77-2.95 (1H, m), 2.40-2.50 (1H, m), 2.12-2.32(2H, m).

MS (ESI) m/z: 438.1 (M+H)⁺.

Ex 62

¹H-NMR (CDCl₃) delta 8.70 (1H, d, J=4.7 Hz), 7.57 (1H, d, J=8.2 Hz),7.46 (1 H, d, J=2.1 Hz), 7.27-7.35 (3H, m), 7.14-7.22 (1H, m), 5.95 (1H, br s), 4.53-4.65 (2 H, m), 4.25-4.42 (2H, m), 4.20 (1H, d, J=11.4Hz), 3.43 (1H, dd, J=12.4, 4.0 Hz), 2.54-2.64 (1H, m) 2.29-2.53 (3H, m),1.25 (1 H, s).

MS (ESI) m/z: 438.1 (M+H)⁺.

The following Examples and Intermediates were prepared by GeneralProcedure M (Tables 33 and 35).

General Procedure M

To a mixture of substrate (1.0 eq.), Chiral Ru Catalyst (5 mol %) andtriethylamine (2.0 eq.) in DMF was added formic acid (5.0 eq.) at 0° C.The mixture was stirred at 0° C. for 10 min, and then warm to roomtemperature. After being stirred at room temperature until completereaction, aq. NaHCO₃ was added to the mixture. The mixture was extractedwith EtOAc twice and washed with water and brine. The extracts werecombined, dried over Na₂SO₄, and concentrated in vacuo. The resultingresidue was purified by silica gel column chromatography and the eachdiastereo isomer was separated by silica gel column chromatographyand/or preparative TLC to afford following Examples.

TABLE 33 Ex- am- Chiral Ru ples Structure Chemical Name SubstrateCatalyst 63

(5S,8S)-N-(2,4-dichloro- 6-methylbenzyl)-8- hydroxy-5,6,7,8- tetrahydro-quinoline-5-carboxamide

RuCl(p- cymene)[(2S,S)- Ts-DPEN] 64

(5R,8S)-N-(2,4-dichloro- 6-methylbenzyl)-8- hydrdroxy-5,6,7,8-tetra-hydroxyquinoline-5- carboxamide 65

(5S,8S)-N-(2,4-dichloro- benzyl)-8-hydroxy-5,6,7,8- tetrahydroquinoline-5-carboxamide

RuCl(p- cymene)[(S,S)- Ts-DPEN] 66

(5R,8S)-N-(2,4-dichloro- benzyl)-8-hydroxy-5,6,7,8- tetrahydroquinoline-5-carboxamide 67

(5S,8S)-N-(2-chloro-4- fluorobenzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline- 5-carboxamide

RuCl(p- cymene)[(S,S)- Ts-DPEN] 68

(5R,8S)-N-(2-chloro-4- fluorobenzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline- 5-carboxamide 69

(5S,8S)-N-(2,4-dichloro- 6-fluorobenzyl)-8-hy- droxy-5,6,7,8-tetrahydro-quinoline-5-carboxamide

RuCl(p- cymene)[(S,S)- Ts-DPEN] 70

(5R,8S)-N-(2,4-dichloro- 6-fluorobenzyl)-8-hy- droxy-5,6,7,8-tetrahydro-quinoline-5-carboxamide 71

(5S,8S)-8-hydroxy-N-(2,3,4- trifluorobenzyl)-5,6,7,8-tetrahydroquinoline- 5-carboxamide

RuCl(p- cymene)[(S,S)- Ts-DPEN] 72

(5R,8S)-8-hydroxy-N-(2,3,4- trifluorobenzyl)-5,6,7,8-tetrahydroquinoline- 5-carboxamide 73

(5R,8S)-8-hydroxy-N-(2,4,6- trifluorobenzyl)-5,6,7,8-tetrahydroquinoline- 5-carboxamide

RuCl(p- cymene)[(S,S)- Ts-DPEN] 74

(5R,8S)-N-(2,4-difluoro- benzyl)-8-hydroxy-5,6,7,8- tetrahydroquinoline-5-carboxamide

RuCl(p- cymene)[(S,S)- Ts-DPEN] 75

(5S,8S)-N-(4-fluoro-2-(tri- fluoromethyl)benzyl)-8-hydroxy-5,6,7,8-tetra- hydroquinoline-5-carbox- amide

RuCl(p- cymene)[(S,S)- Ts-DPEN] 76

(5R,8S)-N-(4-fluoro-2-(tri- fluromethyl)benzyl)-8-hydroxy-5,6,7,8-tetra- hydroquinoline-5- carboxamide 77

(5S,8S)-N-(4-chloro-2- fluorobenzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline- 5-carboxamide

RuCl(p- cymene)[(S,S)- DPEN] 78

(5R,8S)-N-(4-chloro-2- fluorobenzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline- 5-carboxamide 79

(5S,8S)-N-(4-bromo-2- fluorobenzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline- 5-carboxamide

RuCl(p- cymene)[(S,S)- Ts-DPEN] 80

(5R,8S)-N-(4-bromo-2- fluorobenzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline- 5-carboxamide 81

(5S,8S)-N-(2-chloro-3,4- difluorobenzyl)-8-hy- droxy-5,6,7,8-tetrahydro-auinoline-5-carboxamide

RuCl(p- cymene)[(S,S)- Ts-DPEN] 82

(5R,8S)-N-(2-chloro-3,4- difluorobenzyl)-8-hy- droxy-5,6,7,8-tetrahydro-quinoline-5-carboxamide 83

(5S,7S)-N-(2,4-dichloro- 6-methylbenzyl)-7-hy- droxy-5,7-dihydro-5H-cyclopenta[b]pyridin-5- carboxamide

RuCl(p- cymene)[(S,S)- Ts-DPEN] 84

(5R,8R)-N-(2,4-dichloro- 6-methylbenzyl)-8-hy- droxy-5,6,7,8-tetrahydro-quinoline-5-carboxamide

RuCl(p- cymene)[(R,R)- Ts-DPEN] 85

(5S,8R)-N-(2,4-dichloro- 6-methylbenzyl)-8-hy- droxy-5,6,7,8-tetrahydro-quinoline-5-carboxamide 86

(5S,8S)-N-(2-chloro-3- (trifluoromethyl)benzyl)-8-hydroxy-5,6,7,8-tetra- hydroxyqinoline-5- carboxamide

RuCl(p- cymene)[(S,S)- Ts-DPEN] 87

(5R,8R)-N-(2,4-dichloro- benzyl)-8-hydroxy-5,6,7,8- tetrahydroquinoline-5-carboxamide

RuCl(p- cymene)[(R,R)- Ts-DPEN] 88

(5S,8R)-N-(2,4-dichloro- benzyl)-8-hydroxy-5,6,7,8- tetrahydroquinoline-5-carboxamide 89

(5R,8R)-N-(2-chloro-4- fluorobenzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline- 5-carboxamide

RuCl(p- cymene)[(R,R)- Ts-DPEN] 90

(5S,8R)-N-(2-chloro-4- fluorobenzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline- 5-carboxamide 91

(5R,8R)-N-(2,4-dichloro- 6-fluorobenzyl)-8-hy- droxy-5,6,7,8-tetrahydro-quinoline-5-carboxamide

RuCl(p- cymene)[(R,R)- Ts-DPEN] 92

(5S,8R)-N-(2,4-dichloro- 6-fluorobneyzl)-8-hy- droxy-5,6,7,8-tetrahydro-quinoline-5-carboxamide 93

(5R,8R)-8-hydroxy-N-(2,3,4- trifluorobenzyl)-5,6,7,8-tetrahydroquinoline- 5-carboxamide

RuCl(p- cymene)[(R,R)- Ts-DPEN] 94

(5S,8R)-8-hydroxy-N-(2,3,4- trifluorobenzyl)-5,6,7,8-tetrahydroquinoline- 5-carboxamide 95

(5R,8R)-N-(4-chloro-2- fluorobenzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline- 5-carboxamide

RuCl(p- cymene)[(R,R)- Ts-DPEN] 96

(5S,8R)-N-(4-chloro-2- fluorobenzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline- 5-carboxamide 97

(5R,7R)-N-(2,4-dichloro- 6-methylbenzyl)-7-hy- droxy-6,7-dihydro-5H-cyclopenta[b]pyridin-5- carboxamide

RuCl(p- cymene)[(R,R)- Ts-DPEN] 98

(5S,7R)-N-(2,4-dichloro- 6-methylbenzyl)-7-hy- droxy-6,7-dihydro-5H-cyclopenta[b]pyridin-5- carboxamide

TABLE 34 LC MS Examples Method tR (min) [M + H]⁺ 63 A 1.48 365.3 64 A1.47 365.3 65 C 1.40 351.0 66 C 1.39 351.0 67 C 1.28 335.0 68 C 1.28335.0 69 C 1.39 369.0 70 C 1.39 369.0 71 C 1.25 337.0 72 C 1.25 337.0 73C 1.20 337.0 74 C 1.19 319.0 75 C 1.36 369.0 76 C 1.36 369.0 77 C 1.30335.0 78 C 1.30 335.0 79 C 1.33 378.9 80 C 1.33 378.9 81 C 1.31 352.9 82C 1.31 352.9 83 D 1.46 351.0 84 A 1.48 365.3 85 A 1.47 365.2 86 A 1.42385.3 87 C 1.40 351.0 88 C 1.40 351.0 89 C 1.28 335.0 90 C 1.28 335.0 91C 1.39 369.0 92 C 1.38 369.0 93 C 1.25 337.0 94 C 1.25 337.0 95 C 1.30335.0 96 C 1.30 335.0 97 D 1.46 351.0

Ex 63

¹H NMR (DMSO d6) delta 8.42 (1H, d, J 4.6 Hz), 8.37 (1 H, br), 7.49 (1H, br s), 7.37 (1H, d, J=7.9 Hz), 7.36 (1H, br s), 7.23 (1H, dd, J=7.9,4.6 Hz), 5.18 (1H, d, J=4.0 Hz), 4.52 (1H, d, J=4.0 Hz), 4.43 (2H, d,J=4.0 Hz), 3.66 (1H, dd, J=8.6, 5.9 Hz), 2.40 (3 H, s), 2.18-1.99 (2H,m), 1.84-1.79 (2H, m).

Chiral HPLC tR: 28.1 min (Method E), >99% e.e., d.e. Ex 64

¹H NMR (DMSO d6) delta 8.42 (1H, d, J=4.6 Hz), 8.34 (1 H, br), 7.48 (1H, br s), 7.39 (1H, d, J=7.9 Hz), 7.34 (1 H, br s), 7.22 (1H, dd, J=7.9,4.6 Hz), 5.11 (1H, d, J=3.3 Hz), 4.55 (1 H, br), 4.37 (2H, d, J=4.6 Hz),3.73 (1H, dd, J=5.9, 5.9 Hz), 2.36 (3 H, s), 2.22 (1H, m), 2.05 (1H, m),1.84 (1H, m), 1.65 (1H, m).

Chiral HPLC tR: 15.0 min (Method E), >99% e.e., d.e.

Ex 65

¹H NMR (CDCl₃) delta 8.49 (1H, dd, J=4.9, 1.2 Hz), 7.42 (1H, dd, J=7.9,1.2 Hz),7.39 (1H, d, J=1.8 Hz), 7.31 (1H, d, J=8.6 Hz), 7.22 (1H, dd,J=8.6, 1.8 Hz), 7.18 (1H, dd, J=7.9, 4.9 Hz), 6.03 (1 H, br), 4.74 (1H,dd, J=8.6, 5.5 Hz), 4.51 (1 H, dd, J=15.3, 6.1 Hz), 4.46 (1H, dd,J=15.3, 6.1 Hz), 3.72 (1H, dd, J=9.2, 6.1 Hz), 2.38-2.26 (2H, m), 2.06(1H, m), 1.78 (1H, m). A signal due to OH was not observed.

Ex 66

¹H NMR (CDCl₃) delta 8.52 (1H, dd, J=4.9, 1.2 Hz), 7.47 (1H, dd, J=7.9,1.2 Hz),7.36 (1H, d, J=1.8 Hz), 7.26 (1H, d, J=8.6 Hz), 7.21 (1H, m),7.20 (1H, dd, J=7.9, 4.9 Hz),5.84 (1H, br), 4.70 (1H, dd, J=9.2, 5.5Hz), 4.49 (1H, dd, J=14.7, 6.1 Hz), 4.39 (1H, dd, J=14.7, 6.1 Hz), 3.72(1H, dd, J=6.1, 4.3 Hz), 2.37 (1H, m), 2.21 (1H, m), 2.10 (1H, m), 1.90(1H, m). A signal due to OH was not observed.

Ex 67

¹H NMR (CDCl₃) delta 8.49 (1H, dd, J=4.9, 1.2 Hz), 7.42 (1H, d, J=7.9Hz), 7.37 (1H, dd, J=8.6, 6.1 Hz), 7.18 (1H, dd, J=7.9, 4.9 Hz), 7.13(1H, dd, J=7.9, 2.4 Hz), 6.96 (1H, ddd, J=8.6, 7.9, 2.4 Hz), 6.00 (1 H,br), 4.74 (1H, dd, J=9.2, 5.5 Hz), 4.51 (1H, dd, J=15.3, 6.1 Hz), 4.47(1H, dd, J=15.3, 5.5 Hz), 4.12 (1 H, br), 3.73 (1H, dd, J=9.2, 6.1 Hz),2.38-2.23 (2H, m), 2.07 (1H, m), 1.80 (1H, m).

Ex 68

¹H NMR (CDCl₃) delta 8.52 (1H, dd, J=4.9, 1.8 Hz), 7.47 (1H, dd, J=7.9,1.8 Hz),7.32 (1H, dd, J=8.6, 6.1 Hz), 7.21 (1H, dd, J=7.9, 4.9 Hz), 7.09(1H, dd, J=8.6, 2.4 Hz), 6.94 (1H, ddd, J=8.6, 7.9, 2.4 Hz), 5.87 (1 H,br), 4.70 (1H, dd, J=8.6, 5.5 Hz), 4.49 (1H, dd, J=14.7, 6.1 Hz), 4.39(1H, dd, J=14.7, 6.1 Hz), 4.10 (1 H, br), 3.71 (1H, dd, J=6.1, 4.9 Hz),2.36 (1H, m), 2.20 (1H, m), 2.10 (1H, m), 1.90 (1 H, m).

Ex 69

¹H NMR (CDCl₃) delta 8.49 (1H, dd, J=4.9, 1.8 Hz), 7.43 (1H, d, J=7.3Hz), 7.24 (1H, d, J=1.8 Hz), 7.18 (1H, dd, J=7.3, 4.9 Hz), 7.06 (1H, dd,J=9.2, 1.8 Hz), 5.90 (1 H, br), 4.73 (1H, dd, J=9.2, 5.5 Hz), 4.63-4.54(2H, m), 4.12 (1 H, br), 3.70 (1H, dd, J=7.9, 7.3 Hz), 2.37-2.21 (2H,m), 2.06 (1H, m), 1.77 (1H, m).

Ex 70

¹H NMR (CDCl₃) delta 8.51 (1H, dd, J=4.9, 1.2 Hz), 7.47 (1H, dd, J=7.9,1.2 Hz), 7.22-7.19 (2H, m), 7.03 (1H, dd, J=9.2, 1.8 Hz), 5.74 (1 H,br), 4.68 (1 H, dd, J=9.2, 5.5 Hz), 4.60 (1H, ddd, J=14.7, 6.1, 1.2 Hz),4.46 (1H, ddd, J=14.7, 5.5, 1.2 Hz), 4.03 (1 H, br), 3.69 (1H, dd,J=6.1, 4.3 Hz), 2.35 (1H, m), 2.19 (1H, m), 2.08 (1H, m), 1.89 (1H, m).

Ex 71

¹H NMR (CDCl₃) delta 8.50 (1H, d, J=4.9 Hz), 7.41 (1H, d, J=7.9 Hz),7.19 (1H, dd, J=7.9, 4.9 Hz), 7.07 (1H, m), 6.94 (1H, ddd, J=9.2, 6.7,1.8 Hz), 5.94 (1 H, br), 4.74 (1H, dd, J=9.2, 5.5 Hz), 4.50 (1H, dd,J=14.7, 6.1 Hz), 4.46 (1H, dd, J=14.7, 6.1 Hz), 4.09 (1 H, br), 3.73(1H, dd, J=9.2, 6.1 Hz), 2.39-2.23 (2H, m), 2.06 (1H, m), 1.79 (1H, m).

Ex 72

¹H NMR (CDCl₃) delta 8.51 (1H, dd, J=4.9, 1.8 Hz), 7.47 (1H, d, J=7.3Hz), 7.22 (1H, dd, J=7.3, 4.9 Hz), 7.01 (1H, m), 6.93 (1H, m),5.97 (1H,br), 4.71 (1H, dd, J=8.6, 5.5 Hz), 4.46 (1H, dd, J=15.3, 6.1 Hz), 4.40(1H, dd, J=15.3, 6.1 Hz), 4.12 (1 H, br), 3.73 (1H, dd, J=6.1, 4.9 Hz),2.34 (1H, m), 2.22-2.04 (2H, m), 1.93 (1H, m).

Ex 73

¹H NMR (CDCl₃) delta 8.52 (1H, d, J=4.9 Hz), 7.47 (1H, d, J=7.9 Hz),7.21 (1H, dd, J=7.9, 4.9 Hz), 6.66 (2H, dd, J=8.6, 7.9 Hz), 5.75 (1 H,br), 4.69 (1H, dd, J=8.6, 5.5 Hz), 4.52 (1H, ddd, J=14.7, 5.5 Hz), 4.42(1H, dd, J=14.7, 5.5 Hz), 4.10 (1 H, br s), 3.70 (1H, dd, J=5.5, 5.5Hz), 2.34 (1H, m), 2.22 (1H, m), 2.09 (1H, m), 1.91 (1H, m).

Ex 74

¹H NMR (CDCl₃) delta 8.46 (1H, dd, J=4.9, 1.8 Hz), 7.46 (1H, d, J=7.9Hz), 7.25 (1H, m), 7.18 (1H, dd, J=7.9, 4.9 Hz), 6.84-6.74 (2H, m), 6.02(1H, dd, J=5.5, 5.5 Hz),4.69 (1H, dd, J=7.9, 4.9 Hz), 4.43 (1H, dd,J=15.3, 6.1 Hz), 4.37 (1H, dd, J=15.3, 6.1 Hz), 4.16 (1 H, br), 3.70(1H, dd, J=5.5, 5.5 Hz), 2.33 (1H, m), 2.17-2.04 (2H, m), 1.94 (1H, m).

Ex 75

¹H NMR (CDCl₃) delta 8.50 (1H, dd, J=4.9, 1.2 Hz), 7.57 (1H, dd, J=8.6,5.5 Hz),7.40 (1H, dd, J=7.9, 1.2 Hz), 7.37 (1H, dd, J=8.6, 2.4 Hz), 7.23(1H, ddd, J=8.6, 8.6, 2.4 Hz), 7.18 (1H, dd, J=7.9, 4.9 Hz), 6.03 (1 H,br), 4.74 (1H, dd, J=8.6, 5.5 Hz), 4.62 (1H, dd, J=15.3, 6.7 Hz), 4.58(1H, dd, J=15.3, 6.1 Hz), 4.03 (1 H, br), 3.72 (1H, dd, J=8.6, 6.1 Hz),2.35 (1H, m), 2.26 (1H, m), 2.07 (1H, m), 1.79 (1 H, m).

Ex 76

¹H NMR (CDCl₃) delta 8.52 (1H, dd, J=4.9, 1.2 Hz), 7.51 (1H, dd, J=8.6,5.5 Hz), 7.45 (1H, d, J=7.9 Hz), 7.33 (1H, dd, J=8.6, 2.4 Hz), 7.23-7.19(2H, m), 5.74 (1H, br), 4.70 (1H, dd, J=8.6, 5.5 Hz), 4.57 (1H, dd,J=15.3, 6.1 Hz), 4.52 (1H, dd, J=15.3, 6.1 Hz), 3.71 (1H, dd, J=6.1, 4.3Hz), 2.37 (1H, m), 2.21 (1H, m), 2.10 (1H, m), 1.89 (1H, m). A signaldue to OH was not observed.

Ex 77

¹H NMR (CDCl₃) delta 8.47 (1H, dd, J=4.9, 1.2 Hz), 7.41 (1H, d, J=7.9Hz), 7.25 (1H, dd, J=7.9, 6.7 Hz), 7.17 (1H, dd, J=7.9, 4.9 Hz), 7.10(1H, dd, J=7.9, 1.8 Hz), 7.08 (1H, dd, J=7.9, 1.8 Hz), 6.14 (1H, dd,J=6.1, 5.3 Hz), 4.73 (1H, dd, J=9.2, 5.5 Hz), 4.46 (1H, dd, J=15.3, 6.1Hz), 4.43 (1H, dd, J=15.3, 6.1 Hz), 4.26 (1 H, br), 3.71 (1H, dd, J=8.6,6.1 Hz), 2.37-2.21 (2H, m), 2.05 (1H, m), 1.76 (1H, m).

Ex 78

¹H NMR (CDCl₃) delta 8.51 (1H, dd, J=4.9, 1.8 Hz), 7.47 (1H, d, J=7.9Hz), 7.22 (1H, dd, J=7.9, 5.5 Hz), 7.20 (1H, dd, J=7.9, 1.8 Hz),7.10-7.04 (2H, m), 5.80 (1 H, br), 4.70 (1H, dd, J=8.6, 5.5 Hz), 4.45(1H, dd, J=14.7, 6.1 Hz), 4.38 (1 H, dd, J=14.7, 6.1 Hz), 4.11 (1 H,br), 3.71 (1H, dd, J=5.5, 4.9 Hz), 2.35 (1H, m), 2.19 (1 H, m), 2.09(1H, m), 1.91 (1H, m).

Ex 79

¹H NMR (CDCl₃) delta 8.49 (1H, dd, J=4.9, 1.2 Hz), 7.42 (1H, d, J=7.3Hz), 7.27-7.18 (3H, m), 7.18 (1H, dd, J=7.3, 4.9 Hz), 6.01 (1H, br),4.74 (1H, dd, J=8.6, 5.5 Hz), 4.47 (1H, dd, J=14.7, 6.1 Hz), 4.43 (1H,dd, J=14.7, 6.1 Hz), 4.15 (1 H, s), 3.72 (1H, dd, J=8.6, 6.1 Hz),2.38-2.22 (2H, m), 2.06 (1H, m), 1.77 (1H, m).

Ex 80

¹H NMR (CDCl₃) delta 8.50 (1H, dd, J=4.9, 1.2 Hz), 7.46 (1H, d, J=7.3Hz), 7.26-7.13 (4H, m), 5.83 (1 H, br), 4.69 (1H, dd, J=8.6, 7.9 Hz),4.43 (1H, dd, J=15.3, 6.1 Hz), 4.36 (1H, dd, J=15.3, 6.1 Hz), 4.14 (1 H,s), 3.71 (1H, dd, J=5.5, 4.9 Hz), 2.35 (1H, m), 2.24-2.04 (2H, m), 1.90(1H, m).

Ex 81

¹H NMR (CDCl₃) delta 8.51 (1H, d, J=4.9 Hz), 7.44 (1H, d, J=7.9 Hz),7.21 (1H, dd, J=7.9, 4.9 Hz), 7.16 (1H, m), 7.09 (1H, m), 5.95 (1 H,br), 4.76 (1H, dd, J=8.6, 4.9 Hz), 4.54 (1H, dd, J=14.7, 6.1 Hz), 4.50(1H, dd, J=14.7, 6.1 Hz), 3.75 (1H, dd, J=8.6, 6.1 Hz), 3.49 (1 H, s),2.39-2.25 (2H, m), 2.07 (1H, m), 1.81 (1H, m).

Ex 82

¹H NMR (CDCl₃) delta 8.53 (1H, dd, J=4.9, 1.8 Hz), 7.48 (1H, d, J=7.9Hz), 7.23 (1H, dd, J=7.9, 4.9 Hz), 7.12-7.02 (2H, m), 5.86 (1 H, br),4.72 (1H, dd, J=9.2, 5.5 Hz), 4.45 (1H, dd, J=15.3, 6.7 Hz), 4.40 (1H,dd, J=15.3, 6.1 Hz), 3.73 (1 H, dd, J=6.1, 4.2 Hz), 2.90 (1 H, br), 2.36(1H, m), 2.28-2.09 (2H, m), 1.92 (1H, m).

Ex 83

¹H NMR (DMSO d6) delta 8.44 (1 H, br), 8.43 (1H, d, J=4.6 Hz), 7.56 (1H,d, J=7.3 Hz), 7.49 (1H, d, J=2.0 Hz), 7.35 (1H, d, J=2.0 Hz), 7.22 (1H,dd, J=7.3, 4.6 Hz), 5.41 (1H, d, J=5.3 Hz), 5.09 (1H, dd, J=11.9, 5.3Hz), 4.38 (2H, d, J=4.6 Hz), 4.08 (1H, dd, J=7.9, 5.3 Hz), 2.47 (1H, m),2.36 (3 H, s), 1.97 (1H, m).

Ex 84

¹H NMR was identified with the Example 63.

Chiral HPLC tR: 25.1 min (Method E), >99% e.e., d.e.

Ex 85

¹H NMR was identified with the Example 64.

Chiral HPLC tR: 17.9 min (Method E), >99% e.e., d.e.

Ex 86

1H NMR (DMSO d6) delta 8.73 (1 H, br), 8.45 (1H, d, J=4.6 Hz), 7.79 (1H, dd, J=7.9, 1.3 Hz), 7.66 (1H, d, J=7.9 Hz), 7.57 (1H, dd, J=7.9, 7.3Hz), 7.49 (1 H, d, J=7.3 Hz), 7.24 (1H, dd, J=7.9, 4.6 Hz), 5.14 (1H, d,J=4.0 Hz), 4.56 (1 H, br), 4.52-4.43 (2H, m), 3.85 (1H, dd, J=5.9, 5.3Hz), 2.25-2.18 (2H, m), 1.92 (1H, m), 1.69 (1H, m).

Ex 87

¹H NMR was identified with the Example 65.

Ex 88

¹H NMR was identified with the Example 66.

Ex 89

¹H NMR was identified with the Example 67.

Ex 90

¹H NMR was identified with the Example 68.

Ex 91

¹H NMR was identified with the Example 69.

Ex 92

¹H NMR was identified with the Example 70.

Ex 93

¹H NMR was identified with the Example 71.

Ex 94

¹H NMR was identified with the Example 72.

Ex 95

¹H NMR was identified with the Example 77.

Ex 96

¹H NMR was identified with the Example 78.

Ex 97

¹H NMR was identified with the Example 83.

Ex 98

¹H NMR (DMSO d6) delta 8.53 (1 H, br), 8.44 (1H, d, J=4.6 Hz), 7.52 (1H,d, J=7.9 Hz), 7.50 (1H, d, J=2.0 Hz), 7.36 (1H, d, J=2.0 Hz), 7.24 (1H,dd, J=7.9, 4.6 Hz), 5.48 (1H, d, J=7.33 Hz), 4.90 (1H, dd, J=13.8, 6.6Hz), 4.47 (1H, dd, J=14.5, 4.6 Hz),4.40 (1H, dd, J=14.5, 4.6 Hz), 3.82(1H, dd, J=7.3, 7.3 Hz), 2.57 (1 H, m), 2.39 (3 H, s), 2.02 (1H, m).

TABLE 35 Chiral Ru Intermediates Structure Chemical Name SubstrateCatalyst II-d-3

(5R,8S)-methyl 5-fluoro-8-hydroxy-5,6,7,8- tetrahydroquinoline-5-carboxylate

RuCl(p- cymene)[(S,S)- Ts-DPEN] IId--4

(5S,8S)-methyl 5-fluoro-8-hydroxy-5,6,7,8- tetrahydroquinoline-5-carboxylate II-d-5

(5S,8R)-methyl 5-fluoro-8-hydroxy-5,6,7,8- tetrahydroquinoline-5-carboxylate Ru(Cl(p- cymene)[(R,R)- Ts-DPEN] II-d-6

(5R,8R)-methyl 5-fluoro-8-hydroxy-5,6,7,8- tetrahydroquinoline-5-carboxylate II-d-7

(5R,8S)-methyl 3,5-difluoro-8-hydroxy- 5,6,7,8-tetra- hydroquinoline-5-carboxylate

RuCl(p- cymene)[(S,S)- Ts-DPEN] II-d-8

(5S,8S)-methyl 3,5-difluoro-8-hydroxy- 5,6,7,8-tetra- hydroquinoline-5-carboxylate II-d-9

(5R,8S)-methyl 5-fluoro-8-hydroxy-3- methyl-5,6,7,8-tetra-hydroquinoline- 5-carboxylate

RuCl(p- cymene)[(S,S)- Ts-DPEN] II-d-10

(5S,8S)-methyl 5-fluoro-8-hydroxy-3- methyl-5,6,7,8-tetra-hydroquinoline-5- carboxylate

IM II-d-4

¹H NMR (CDCl₃) delta 8.62 (1H, br d, J=4.3 Hz), 7.79 (1H, d, J=7.9 Hz),7.31 (1 H, dd, J=7.9, 4.3 Hz), 4.80 (1H, m), 4.06 (1H, br), 3.81, (3 H,s), 2.74-2.65 (1H, m), 2.45-2.39 (1H, m), 2.27-2.13 (2H, m).

MS (ESI) m/z: 226.1 (M+H)⁺.

Chiral HPLC tR: 34.6 min (Method F), >99% e.e., d.e.

IM II-d-5

¹H NMR and LCMS were identified with the IM II-d-3.

Chiral HPLC tR: 12.2 min (Method F), >99% e.e., d.e.

IM II-d-6

¹H NMR and LCMS were identified with the IM II-d-4.

Chiral HPLC tR: 13.9 min (Method F), >99% e.e., d.e.

IM II-d-7

¹H NMR (CDCl₃) delta 8.50 (1H, m), 7.43 (1H, dd, J=7.3, 2.4 Hz), 4.72(1H, m), 3.97 (1 H, br), 3.85 (3 H, s), 2.52-2.33 (3H, m), 2.03 (1H, m).

MS (ESI) m/z: 244.0 (M+H)⁺.

Chiral HPLC tR: 7.3 min (Method H), 98.8% e.e., >99% d.e

IM II-d-8 ¹H NMR (CDCl₃) delta 8.49 (1H, m), 7.52 (1H, dd, J=8.5, 2.4Hz), 4.78 (1H, m), 3.83 (3H, s), 3.69 (1H, s), 2.54 (1H, m), 2.41 (1H,m), 2.26-2.11 (2H, m).

MS (ESI) m/z: 244.0 (M+H)⁺.

Chiral HPLC tR: 9.6 min (Method H), 97.5% e.e., 97.1% d.e.

IM II-d-9 ¹H NMR (CDCl₃) delta 8.44 (1H, s), 7.49 (1H, s), 4.73 (1H, m),4.34 (1 H, br), 3.83 (3 H, s), 2.48-2.32 (3H, m), 2.35 (3 H, s), 2.02(1H, m).

MS (ESI) m/z: 238.2 (M+H)⁺.

Chiral HPLC tR: 15.4 min (Method G), 98.6% e.e., 97.0% d.e.

IM II-d-10 ¹H NMR (CDCl₃) delta 8.43 (1H, s), 7.56 (1H, s), 4.79 (1H,m), 3.82 (3 H, s), 2.68 (1H, m), 2.37 (1H, m), 2.35 (3 H, s), 2.24-2.11(2H, m), 1.86 (1 H, br).

MS (ESI) m/z: 238.2 (M+H)⁺.

Chiral HPLC tR: 10.4 min (Method G), >99% e.e., 96.4% d.e.

The following Examples were prepared by General Procedure A (Table 36).

TABLE 36-1 Examples Structure Chemical Name Substrate Amine 99

(5R,8S)-N-(2,4-dichloro- 6-methylbenzyl)-5- fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline- 5-carboxamide

100

(5S,8R)-N-(2,4-dichloro- 6-methylbenzyl)-5- fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline- 5-carboxamide

101

(5R,8S)-N-(2-chloro-3- (trifluoromethyl)benzyl)- 5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline- 5-carboxamide

102

(5S,8R)-N-(2-chloro-3- (trifluoromethyl)benzyl)- 5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline- 5-carboxamide

103

(5R,8S)-N-(2,4-dichloro- 6-hydroxymethylbenzyl)-5-fluoro-8-hydroxy-5,6,7,8- tetrahydroquinoline- 5-carboxamide

104

(5R,8R)-N-(2,4-dichloro- 6-hydroxymethyl)benzyl)-5-fluoro-8-hydroxy-5,6,7,8- tetrahydroquinoline- 5-carboxamide

105

(5R,8S)-N-(2,4-dichloro benzyl)-5-fluoro-8-hydroxy- 5,6,7,8-tetrahydroquinoline- 5-carboxamide

106

(5S,8R)-N-(2,4-dichloro benzyl)-5-fluoro-8-hydroxy- 5,6,7,8-tetrahydroquinoline- 5-carboxamide

107

(5S,8R)-N-(2-chloro-4- fluorobenzyl)- 5-fluoro-8- hydroxy-5,6,7,8-tetrahydroquinoline- 5-carboxamide

108

(5S,8R)-5-fluoro-8-hydroxy- N-(2,3,4-trifluorobenzyl)- 5,6,7,8-tetrahydroquinoline- 5-carboxamide

109

(5S,8R)-N-(2,4-difluoro- benzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline- 5-carboxamide

110

(5S,8R)-5-fluoro-N-(4- fluoro-2-(trifluoromethyl)benzyl)-8-hydroxy-5,6,7,8- tetrahydroquinoline- 5-carboxamide

111

(5S,8R)-N-(4-chloro-2- fluorobenzyl)-5-fluoro-8- hydroxy-5,6,7,8-tetrahydroquinoline-5- carboxamide

112

(5R,8S)-N-(2,6-dichloro- 4-(trifluoromethyl)benzyl)-5-fluoro-8-hydroxy-5,6,7,8- tetrahydroquinoline- 5-carboxamide

113

(5S,8R)-N-(2,6-dichloro- 4-(trifluoromethyl)benzyl)-5-fluoro-8-hydroxy-5,6,7,8- tetrahydroquinoline- 5-carboxamide

114

(5R,8S)-N-(2,4-dichloro- 6-(trifluoromethyl)benzyl)-5-fluoro-8-hydroxy-5,6,7,8- tetrahydroquinoline- 5-carboxamide

115

(5S,8R)-N-(2,4-dichloro- 6-(trifluoromethyl)benzyl)-5-fluoro-8-hydroxy-5,6,7,8- tetrahydroquinoline- 5-carboxamide

116

(5R,8S)-N-(2,4-dichloro- 6-fluorobenzyl)- 5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline- 5-carboxamide

117

(5S,8R)-N-(2,4-dichloro- 6-fluorobenzyl)- 5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline- 5-carboxamide

118

(5S,8R)-N-(4-bromo-2- chlorobenzyl)-5-fluoro- 8-hydroxy-5,6,7,8-tetrahydroquinoline-5- carboxamide

119

(5S-8R)-N-((R)-1-(2,4- dichlorophenyl)ethyl)-5-fluoro-8-hydroxy-5,6,7,8- tetrahydroquinoline- 5-carboxamide

120

(5R,8S)-N-(2,3-dichloro benzyl)-5-fluoro-8- hydroxy-5,6,7,8-tetrahydroquinoline- 5-carboxamide

121

(5S,8RS)-N-(2,3-dichloro benzyl)-5-fluoro-8- hydroxy-5,6,7,8-tetrahydroquinoline- 5-carboxamide

122

(5S,8R)-N-(2-chloro-6- methylbenzyl)-5-fluoro- 8-hydroxy-5,6,7,8,-tetrahydroquinoline- 5-carboxamide

123

(5S,8R)-N-(2-chloro-4,5- difluorobenzyl)-5-fluoro- 8-hydroxy-5,6,7,8,-tetrahydroqunioline- 5-carboxamide

124

(5S,8R)-5-fluoro-8-hydroxy- N-(2,3,6-trichlorobenzyl)- 5,6,7,8,-tetrahydroquinoline- 5-carboxamide

125

(5S,8R)-N-(2-chloro-4- methylbenzyl)-5-fluoro- 8-hydroxy-5,6,7,8-hydroquinoline- 5-carboxamide

TABLE 37 LC MS Examples Method tR (min) [M + H]⁺ 99 A 1.61 383.0 101 A1.52 403.1 102 A 1.52 403.1 105 A 1.51 369.1 106 A 1.51 369.1 107 A 1.39353.1 108 C 1.35 354.9 109 C 1.30 337.0 110 C 1.47 386.9 111 C 1.41352.9 112 A 1.62 437.0 113 A 1.62 437.1 114 A 1.61 419.1 115 A 1.61419.1 116 C 1.50 386.9 117 C 1.49 386.9 118 A 1.54 413.0 119 A 1.58383.2 120 A 1.47 369.1 121 A 1.47 369.1 122 A 1.45 349.2 123 A 1.42371.2 124 A 1.54 403.1 125 A 1.47 349.2

Ex 99

¹H NMR (CDCl₃) delta 8.60 (1H, ddd, J=4.6, 2.0, 1.3 Hz), 7.49 (1H, ddd,J=7.9, 2.0, 1.3 Hz), 7.33 (1H, d, J=2.0 Hz), 7.25 (1H, dd, J=7.9, 4.6Hz), 7.16 (1H, d, J=2.0 Hz), 7.08 (1 H, br), 4.76 (1H, dd, J=5.3, 5.3Hz), 4.73 (1H, dd, J=13.8, 5.3 Hz), 4.63 (1H, dd, J=13.8, 5.3 Hz), 4.35(1 H, s), 2.66-2.23 (3H, m), 2.48 (3 H, s), 2.00 (1 H, m).

Chiral HPLC tR: 11.5 min (Method I), >99% e.e., d.e.

Ex 100

¹H NMR and LCMS were identified with the Example 99.

Chiral HPLC tR: 15.2 min (Method I), >99% e.e., d.e.

Ex 101

¹H NMR (CDCl₃) delta 8.61 (1H, br d, J=4.6 Hz), 7.71 (1H, d, J=7.3 Hz),7.65 (1 H, d, J=7.9 Hz), 7.49 (1H, ddd, J=7.9, 2.0, 1.3 Hz), 7.41 (1H,dd, J=7.9, 7.3 Hz), 7.32 (1 H, br), 7.24 (1H, dd, J=7.9, 4.6 Hz),4.79-4.71 (3H, m), 4.35 (1 H, s), 2.57 (1 H, m), 2.44-2.27 (2H, m), 2.03(1H, m).

Chiral HPLC tR: 20.7 min (Method K), >99% e.e., d.e.

Ex 102

¹H NMR was identified with the Example 101.

Chiral HPLC tR: 29.8 min (Method K), >99% e.e., d.e.

Ex 103

¹H NMR (CDCl₃) delta 8.60 (1H, br d, J=4.6 Hz), 7.65 (1 H, br), 7.45(1H, d, J=2.0 Hz),7.42 (1H, d, J=7.9 Hz), 7.34 (1H, d, J=2.0 Hz), 7.23(1H, dd, J=7.9, 4.6 Hz), 4.83-4.65 (5H, m), 4.32 (1 H, s), 3.82 (1 H,br), 2.52 (1H, m), 2.42-2.21 (2 H, m), 2.00 (1H, m).

MS (ESI) m/z: 399.0 (M+H)⁺. Chiral HPLC tR: 12.2 min (Method J), >99%e.e., d.e. Ex 104

¹H NMR and LCMS were identified with the Example 103.

Chiral HPLC tR: 16.4 min (Method J), >99% e.e., d.e.

Ex 107

¹H NMR (CDCl₃) delta 8.60 (1H, ddd, J=4.9, 1.8, 1.2 Hz), 7.49 (1H, ddd,J=7.9, 1.8, 1.2 Hz), 7.41 (1H, dd, J=8.6, 6.1 Hz), 7.25-7.22 (1 H, br),7.24 (1H, dd, J=7.9, 4.9 Hz), 7.19 (1H, dd, J=8.6, 2.4 Hz), 7.00 (1H,ddd, J=8.6, 7.9, 2.4 Hz), 4.74 (1H, m), 4.65 (1H, dd, J=14.7, 6.1 Hz),4.59 (1H, dd, J=14.7, 6.1 Hz), 4.46 (1 H, br s), 2.61-2.28 (3H, m), 2.02(1H, m).

Ex 108

¹H NMR (CDCl₃) delta 8.61 (1H, br d, J=4.9 Hz), 7.48 (1H, br d, J=7.9Hz), 7.26 (1H, dd, J=7.9, 4.9 Hz), 7.23 (1 H, br), 7.12 (1H, m), 6.98(1H, m), 4.75 (1H, m), 4.65 (1H, dd, J=14.7, 6.1 Hz), 4.57 (1H, dd,J=14.7, 6.1 Hz), 4.40 (1 H, br s), 2.61-2.28 (3H, m), 2.02 (1H, m).

Ex 109

¹H NMR (CDCl₃) delta 8.60 (1H, br d, J=4.9 Hz), 7.48 (1H, br d, J=7.9Hz), 7.36 (1H, m), 7.26-7.23 (1 H, br), 7.24 (1H, dd, J=7.9, 4.9 Hz),6.91-6.84 (2H, m), 4.75 (1H, m),4.62 (1H, dd, J=14.7, 6.1 Hz), 4.53 (1H,dd, J=14.7, 5.5 Hz), 4.49 (1H, br s), 2.61-2.27 (3H, m), 2.02 (1H, m).

Ex 111

¹H NMR (CDCl₃) delta 8.60 (1H, br d, J=4.9 Hz), 7.48 (1H, br d, J=7.9Hz), 7.32 (1H, dd, J=7.9, 7.9 Hz), 7.25 (1H, dd, J=7.9, 4.9 Hz), 7.21(1H, br), 7.16-7.14 (2 H, m), 4.74 (1H, m), 4.62 (1H, dd, J=15.3, 6.1Hz), 4.54 (1H, dd, J=15.3, 5.5 Hz), 4.43 (1 H, br s), 2.61-2.27 (3H, m),2.01 (1H, m).

Ex 116

¹H NMR (CDCl₃) delta 8.60 (1H, ddd, J=4.9, 1.8, 1.2 Hz), 7.52 (1H, ddd,J=7.9, 1.8, 1.2 Hz), 7.29 (1H, dd, J=1.8, 1.8 Hz), 7.25 (1H, dd, J=7.9,4.9 Hz), 7.14-7.08 (1 H, br), 7.11 (1H, ddd, J=9.2, 1.8, 1.8 Hz),4.79-4.63 (3H, m), 4.46 (1 H, br), 2.61-2.26 (3H, m), 2.02 (1H, m).

Ex 117

¹H NMR was identified with the Example 116.

EX 119

¹H NMR (CDCl₃) delta 8.57 (1H, br d, J=4.9 Hz), 7.44 (1H, d, J=1.8 Hz),7.43 (1 H, br d, J=7.9 Hz), 7.37 (1H, d, J=8.6 Hz), 7.30 (1H, dd, J=8.6,1.8 Hz), 7.20 (1 H, dd, J=7.9, 4.9 Hz), 7.17 (1 H, br), 5.45 (1H, m),4.73 (1H, m), 4.38 (1 H, br), 2.62-2.30 (3H, m), 2.02 (1H, m), 1.59 (3H,d, J=7.3 Hz).

The following Examples and Intermediates were prepared by GeneralProcedure N (Tables 38 and 40).

General Procedure N

A mixture of substrate (1.0 eq.) and 2 N aq. NaOH (2.0 eq.) in MeOH wasstirred at room temperature for 1.5 h, 2 N hydrochloric acid (2.2 eq.)was added to the mixture. The mixture was concentrated in vacuo. Tolueneand MeCN was added to the resulting mixture and concentrated in vacuo.This procedure was repeated 3 times to remove remaining water. Theresidual powder was dissolved with THF and amine (1.1 eq.),triethylamine (1.3 eq.), and DMT-MM (1.8 eq.) were added to the mixtureat ambient temperature. After being stirred until complete reaction, theinsoluble material was removed by filtration, and the filtrate wasconcentrated in vacuo. The resulting residue was purified by silica gelcolumn chromatography, and/or SCX cartridge column, and then preparativeHPLC to afford the following Examples and Intermediates.

TABLE 38 Ex- am- ples Structure Chemical Name Substrate Amine 126

(5R,8R)-N-(2,4- dichloro-6- methylbenzyl)- 5-fluoro- 8-hydroxy-5,6,7,8-tetrahydroquinoline- 5-carboxamide

127

(5S,8S)-N-(2,4- dichloro-6- methylbenzyl)-fluoro- 8-hydroxy-5,6,7,8-tetrahydroquinoline- 5-carboxamide

128

(5R,8R)-N-(2- chloro-3- (trifluoromethyl) benzyl)-5-fluoro-8-hydroxy-5,6,7,8- tetrahydroquinoline- 5-carboxamide

129

(5S,8S)-N-(2- chloro-3- (trifluoromethyl) benzyl)-5-fluoro-8-hydroxy-5,6,7,8- tetrahydroquinoline- 5-carboxamide

130

(5R,8R)-N-(2,4- dichloro-6- (hydroxymethyl) benzyl)-5-fluoro-8-hydroxy-5,6,7,8- tetrahydroquinoline- 5-carboxamide

131

(5S,8S)-N-(2,4- dichloro-6- (hydroxymethyl) benzyl)-5- fluoro-8-hydroxy-5,6,7,8- tetrahydroquinoline- 5-carboxamide

132

(5R,8R)-N-(2,4- dichlorobenzyl)- 5-fluoro-8- hydroxy-5,6,7,8-tetrahydroquinoline- 5-carboxamide

133

(5S,8S)-N-(2,4- dichlorobenzyl)-5- fluoro-8-hydroxy- 5,6,7,8-tetrahydroquinoline- 5-carboxamide

134

(5R,8R)-N-(2- chloro-4- fluorobenzyl)- 5-fluoro-8- hydroxy-5,6,7,8-tetrahydroquinoline- 5-carboxamide

135

(5S,8S)-N-(2- chloro-4- fluorobenzyl)- 5-fluoro-8- hydroxy-5,6,7,8-tetrahydroquinoline- 5-carboxamide

136

(5R,8R)-5-fluoro-8- hydroxy-N-(2,3,4- trifluorobenzyl)- 5,6,7,8-tetrahydroquinoline- 5-carboxamide

137

(5S,8S)-5-fluoro-8- hydroxy-N-(2,3,4- trifluorobenzyl)- 5,6,7,8-tetrahydroquinoline- 5-carboxamide

138

(5R,8R)-N-(2,6- dichlorobenzyl)- 5-fluoro-8- hydroxy-5,6,7,8-tetrahydroquinoline- 5-carboxamide

139

(5S,8S)-N-(2,6- dichlorobenzyl)- 5-fluoro-8- hydroxy-5,6,7,8-tetrahydroquinoline- 5-carboxamide

140

(5R,8R)-N-(2,4- difluorobenzyl)- 5-fluoro-8- hydroxy-5,6,7,8-tetrahydroquinoline- 5-carboxamide

141

(5S,8S)-N-(2,4- difluorobenzyl)- 5-fluoro-8- hydroxy-5,6,7,8-tetrahydroquinoline- 5-carboxamide

142

(5S,8S)-N-(2- chloro-6- fluoro-3- methylbenzyl)-5- fluoro-8-hydroxy-5,6,7,8- tetrahydroquinoline- 5-carboxamide

143

(5R,8R)-5-fluoro- N-(4-fluoro-2- (trifluoromethyl) benzyl)-8-hydroxy-5,6,7,8- tetrahydroquinoline- 5-carboxamide

144

(5S,8S)-5-fluoro- N-(4-fluoro-2- (trifluoromethyl) benzyl)-8-hydroxy-5,6,7,8- tetrahydroquinoline- 5-carboxamide

145

(5R,8R)-N-(4- chloro-2- fluorobenzyl)- 5-fluoro-8- hydroxy-5,6,7,8-tetrahydroquinoline- 5-carboxamide

146

(5S,8S)-N-(4- chloro-2- fluorobenzyl)- 5-fluoro-8- hydroxy-5,6,7,8-tetrahydroquinoline- 5-carboxamide

147

(5R,8R)-N-(2,6- dichloro-4- (trifluoromethyl) benzyl)-5-fluoro-8-hydroxy-5,6,7,8- tetrahydroquinoline- 5-carboxamide

148

(5S,8S)-N-(2,6- dichloro-4- (trifluoromethyl) benzyl)-5-fluoro-8-hydroxy-5,6,7,8- tetrahydroquinoline- 5-carboxamide

149

(5S,8S)-N-(2,4- dichloro-6- (difluoromethyl) benzyl)-5-fluoro-8-hydroxy-5,6,7,8- tetrahydroquinoline- 5-carboxamide

150

(5S,8S)-N-(2-chloro- 4-fluoro-6- (hydroxymethyl) benzyl)-5-fluoro-8-hydroxy-5,6,7,8- tetrahydroquinoline- 5-carboxamide

151

(5R,8R)-N-(2,4- dichloro-6- fluorobenzyl)- 5-fluoro-8- hydroxy-5,6,7,8-tetrahydroquinoline- 5-carboxamide

152

(5S,8S)-N-(2,4- dichloro-6- fluorobenzyl)- 5-fluoro- 8-hydroxy-5,6,7,8-tetrahydroquinoline- 5-carboxamide

153

(5R,8R)-N-(4- bromo-2- chlorobenzyl)- 5-fluoro-8- hydroxy-5,6,7,8-tetrahydroquinoline- 5-carboxamide

154

(5S,8S)-N-(4- bromo-2- chlorobenzyl)- 5-fluoro-8- hydroxy-5,6,7,8-tetrahydroquinoline- 5-carboxamide

155

(5R,8R)-N- ((R)-1-(2,4- dichlorophenyl) ethyl)-5-fluoro-8-hydroxy-5,6,7,8- tetrahydroquinoline- 5-carboxamide

156

(5R,8R)-N- (4-chloro-2- (trifluoromethyl) benzyl)-5-fluoro-8-hydroxy-5,6,7,8- tetrahydroquinoline- 5-carboxamide

157

(5S,8S)-N- (4-chloro-2- (trifiuoromethyl) benzyl)-5-fluoro-8-hydroxy-5,8,7,8- tetrahydroquinoline- 5-carboxamide

158

(5R,8R)-N-(2,3- dichlorobenzyl)- 5-fluoro-8- hydroxy-5,6,7,8-tetrahydroquinoline- 5-carboxamide

159

(5S,8S)-N-(2,3- dichlorobenzyl)- 5-fluoro-8- hydroxy-5,6,7,8-tetrahydroquinoline- 5-carboxamide

160

(5R,8R)-N-(2- chloro-6- methylbenzyl)- 5-fluoro-8- hydroxy-5,6,7,8-tetrahydroquinoline- 5-carboxamide

161

(5S,8S)-N-(2- chloro-6- methylbenzyl)- 5-fluoro- 8-hydroxy-5,6,7,8-tetrahydroquinoline- 5-carboxamide

162

(5R,8R)-N-(2- chloro-4,5- difluorobenzyl)-5- fluoro-8- hydroxy-5,6,7,8-tetrahydroquinoline- 5-carboxamide

163

(5S,8S)-N-(2- chloro-4,5- difluorobenzyl)- 5-fluoro-8- hydroxy-5,6,7,8-tetrahydroquinoline- 5-carboxamide

164

(5R,8R)-5-fluoro-8- hydroxy-N-(2,3,6- trichlorobenzyl)- 5,6,7,8-tetrahydroquinoline- 5-carboxamide

165

(5S,8S)-5-fluoro-8- hydroxy-N-(2,3,6- trichlorobenzyl)- 5,6,7,8-tetrahydroquinoline- 5-carboxamide

166

(5R,8R)-N-(2- chloro-4- methylbenzyl)- 5-fluoro- 8-hydroxy-5,6,7,8-tetrahydroquinoline- 5-carboxamide

167

(5S,8S)-N-(2- chloro-4- methylbenzyl)- 5-fluoro-8- hydroxy-5,6,7,8-tetrahydroquinoline- 5-carboxamide

168

(5S,8S)-5-fluoro-8- hydroxy-N- ((S)-1-(2,3,4- trichlorophenyl)ethyl)-5,6,7,8- tetrahydroquinoline- 5-carboxamide

169

(5S,8S)-N-(2- chloro-3- fluorobenzyl)- 5-fluoro-8- hydroxy-5,6,7,8-tetrahydroquinoline- 5-carboxamide

170

(5S,8S)-N-(2- chloro-3,6- difluorobenzyl)- 5-fluoro-8- hydroxy-5,6,7,8-tetrahydroquinoline- 5-carboxamide

171

(5S,8S)-N- (2-chloro-6- fluorobenzyl)- 5-fluoro-8- hydroxy-5,6,7,8-tetrahydroquinoline- 5-carboxamide

172

(5S,8S)-N- (2-chloro-4- methoxybenzyl)- 5-fluoro- 8-hydroxy-5,6,7,8-tetrahydroquinoline- 5-carboxamide

173

(5S,8S)-N-(2,5- dichlorobenzyl)- 5-fluoro-8- hydroxy-5,6,7,8-tetrahydroquinoline- 5-carboxamide

174

(5S,8S)-N-(2- chloro-3,4- difluorobenzyl)- 5-fluoro- 8-hydroxy-5,6,7,8-tetrahydroquinoline- 5-carboxamide

175

(5S,8S)-5-fluoro- N-(2-fluoro-3- (trifluoromethyl) benzyl)-8-hydroxy-5,6,7,8- tetrahydroquinoline- 5-carboxamide

176

(5S,8S)-N-(2- chloro-4,6- difluorobenzyl)- 5-fluoro-8- hydroxy-5,6,7,8-tetrahydroquinoline- 5-carboxamide

177

(5S,8S)-N-((3,5- dichloropyridin-2- yl)methyl)-5- fluoro-8-hydroxy-5,6,7,8- tetrahydroquinoline- 5-carboxamide

178

(58,8S)-5-fluoro- N-(3-fluoro-2- (trifluoromethyl) benzyl)-8-hydroxy-5,6,7,8- tetrahydroquinoline- 5-carboxamide

179

(5S,8S)-N-(2- chloro-6- (trifluoromethyl) benzyl)-5-fluoro-8-hydroxy-5,6,7,8- tetrahydroquinoline- 5-carboxamide

180

(5S,8S)-5-fluoro-8- hydroxy-N-(2,4,6- trifluorobenzyl)- 5,6,7,8-tetrahydroquinoline- 5-carboxamide

181

(5S,8S)-N- (5-bromo-2- chlorobenzyl)- 5-fluoro- 8-hydroxy-5,6,7,8-tetrahydroquinoline- 5-carboxamide

182

(5S,8S)-N-(4- bromo-2- fluorobenzyl)- 5-fluoro-8- hydroxy-5,6,7,8-tetrahydroquinoline- 5-carboxamide

183

(5S,8S)-N-(4-chloro- 2,3-difluorobenzyl)- 5-fluoro-8- hydroxy-5,6,7,8-tetrahydroquinoline- 5-carboxamide

184

(5S,8S)-N-(4- chloro-2,6- difluorobenzyl)- 5-fluoro-8- hydroxy-5,6,7,8-tetrahydroquinoline- 5-carboxamide

185

(5S,8S)-N-(3- chloro-2,4- difluorobenzyl)- 5-fluoro-8- hydroxy-5,6,7,8-tetrahydroquinoline- 5-carboxamide

186

(5S,8S)-5-fluoro- N-(2-fluoro-6- (trifluoromethyl) benzyl)-8-hydroxy-5,6,7,8- tetrahydroquinoline- 5-carboxamide

187

(5S,8S)-N- (2-chloro-4- (trifluoromethyl) benzyl)-5-fluoro-8-hydroxy-5,6,7,8- tetrahydroquinoline- 5-carboxamide

188

(5S,8S)-N- (3-chloro-4- fluorobenzyl)- 5-fluoro-8- hydroxy-5,6,7,8-tetrahydroquinoline- 5-carboxamide

189

(5S,8S)-5-fluoro-8- hydroxy-N- ((R)-1,2,3,4- tetrahydronaphthalen-1-yl)-5,6,7,8- tetrahydroquinoline 5-carboxamide

190

(5S,8S)-N- (3-chloro-2- fluorobenzyl)- 5-fluoro-8- hydroxy-5,6,7,8-tetrahydroquinoline- 5-carboxamide

191

(5S,8S)-N-(2,4- dichlorophenethyl)- 5-fluoro- 8-hydroxy-5,6,7,8-tetrahydroquinoline- 5-carboxamide

192

(5S,8S)-5-fluoro-8- hydroxy-N-((1- morpholinocyclohexyl)methyl)-5,6,7,8- tetrahydroquinoline- 5-carboxamide

193

(5S,8S)-N-(3-chloro- 2,6-difluorobenzyl)- 5-fluoro-8- hydroxy-5,6,7,8-tetrahydroquinoline- 5-carboxamide

194

(5S,8S)-N- ((3-chloro-5- (trifluoromethyl) pyridin-2-yl)methyl)-5-fluoro-8- hydroxy-5,6,7,8- tetrahydroquinoline- 5-carboxamide

195

(5S,8S)-N-(2- chlorobenzyl)- 5-fluoro-8-hydroxy- 5,6,7,8-tetrahydroquinoline- 5-carboxamide

196

(5S,8S)-N-((R)-2,3- dihydro-1H- inden-1-yl)-5- fluoro-8-hydroxy-5,6,7,8- tetrahydroquinoline- 5-carboxamide

197

(5S,8S)-N-(3,4- dichlorobenzyl)- 5-fluoro-8- hydroxy-5,6,7,8-tetrahydroquinoline- 5-carboxamide

198

(5S,8S)-N-(2- chloro-6- methoxybenzyl)- 5-fluoro-8- hydroxy-5,6,7,8-tetrahydroquinoline- 5-carboxamide

199

(5S,8S)-5-fluoro-8- hydroxy-N-(2- (trifluoromethyl) benzyl)-5,6,7,8-tetrahydroquinoline- 5-carboxamide

200

(5S,8S)-5-fluoro-8- hydroxy-N-(3,4,5- trifluorobenzyl)- 5,6,7,8-tetrahydroquinoline- 5-carboxamide

201

(5S,8S)-N- (4-cyano-2- fluorobenzyl)- 5-fluoro-8- hydroxy-5,6,7,8-tetrahydroquinoline- 5-carboxamide

202

(5S,8S)-N-(3,4- difluorobenzyl)- 5-fluoro-8- hydroxy-5,6,7,8-tetrahydroquinoline- 5-carboxamide

203

(5S,8S)-N- (3-chloro-5- fluorobenzyl)- 5-fluoro-8- hydroxy-5,6,7,8-tetrahydroquinoline- 5-carboxamide

204

(5S,8S)-N- (2-chloro-5- fluorobenzyl)- 5-fluoro-8- hydroxy-5,6,7,8-tetrahydroquinoline- 5-carboxamide

205

(5S,8S)-N-(3- chlorobenzyl)- 5-fluoro- 8-hydroxy-5,6,7,8-tetrahydroquinoline- 5-carboxamide

206

(5S,8S)-N- (4-chloro-3- fluorobenzyl)- 5-fluoro-8- hydroxy-5,6,7,8-tetrahydroquinoline- 5-carboxamide

207

(5S,8S)-5-fluoro- N-(2-fluoro-4- (trifluoromethoxy) benzyl)-8-hydroxy-5,6,7,8- tetrahydroquinoline- 5-carboxamide

208

(5S,8S)-N-(2,3- difluorobenzyl)- 5-fluoro-8- hydroxy-5,6,7,8-tetrahydroquinoline- 5-carboxamide

209

(5S,8S)-N- (2-chloro-5- (trifluoromethyl) benzyl)-5-fluoro-8-hydroxy-5,6,7,8- tetrahydroquinoline 5-carboxamide

210

(5S,8S)-N-(4- chlorobenzyl)- 5-fluoro-8- hydroxy-5,6,7,8-tetrahydroquinoline- 5-carboxamide

211

(5S,8S)-5-fluoro-8- hydroxy-N- (4-methoxy- 2-(trifluoromethyl)benzyl)-5,6,7,8- tetrahydroquinoline- 5-carboxamide

212

(5S,8S)-N-(3,5- dichlorobenzyl)- 5-fluoro-8- hydroxy-5,6,7,8-tetrahydroquinoline- 5-carboxamide

213

(5S,8S)-N-((4-(4- chlorophenyl) thiazol-2- yl)methyl)-5-fluoro-8-hydroxy-5,6,7,8- tetrahydroquinoline- 5-carboxamide

214

(5S,8S)-5-fluoro-8- hydroxy-N-(2- (morpholinomethyl) benzyl)-5,6,7,8-tetrahydroquinoline- 5-carboxamide

215

(5S,8S)-5-fluoro-8- hydroxy-N- ((1S,2R)-2- phenylcyclopropyl)- 5,6,7,8-tetrahydroquinoline- 5-carboxamide

216

(5S,8S)-N-(6-chloro- 2-fluoro-3- methylbenzyl)-5- fluoro-8-hydroxy-5,6,7,8- tetrahydroquinoline- 5-carboxamide

217

(5S,8S)-N-(2,6- difluorobenzyl)-5- fluoro-8-hydroxy- 5,6,7,8-tetrahydroquinoline- 5-carboxamide

218

(5S,8S)-5-fluoro-8- hydroxy-N- ((S)-1,2,3,4- tetrahydronaphthalen-1-yl)-5,6,7,8- tetrahydroquinoline- 5-carboxamide

219

(5S,8S)-5-fluoro-8- hydroxy-N-(2-(3- trifluoromethyl) phenoxy)ethyl)-5,6,7,8- tetrahydroquinoline- 5-carboxamide

220

(5S,8S)-5-fluoro- N-((1-(4- fluorophenyl) cyclopropyl)methyl)-8-hydroxy-5,6,7,8- tetrahydroquinoline- 5-carboxamide

221

(5S,8S)-N-(3,5- difluorobenzyl)- 5-fluoro-8- hydroxy-5,6,7,8-tetrahydroquinoline- 5-carboxamide

222

(5S,8S)-5-fluoro-8- hydroxy-N- ((1R,2S)-2- phenylcyclopropyl)- 5,6,7,8-tetrahydroquinoline- 5-carboxamide

223

(5S,8S)-5- fluoro-N-(2- fluorobenzyl)-8- hydroxy-5,6,7,8-tetrahydroquinoline- 5-carboxamide

224

(5S,8S)-N- (2-chloro-3- methoxybenzyl)-5- fluoro-8- hydroxy-5,6,7,8-tetrahydroquinoline- 5-carboxamide

225

(5S,8S)-N- ((1S,2S)-2- (benzyloxy) cyclopentyl)- 5-fluoro-8-hydroxy-5,6,7,8- tetrahydroquinoline- 5-carboxamide

226

(5S,8S)-N-((S)-2,3- dihydro-1H- inden-1-yl)-5- fluoro-8-hydroxy-5,6,7,8- tetrahydroquinoline- 5-carboxamide

227

(5S,8S)-N-(3,3- dimethylbutyl)- 5-fluoro- 8-hydroxy-5,6,7,8-tetrahydroquinoline- 5-carboxamide

228

(5S,8S)-5-fluoro-8- hydroxy-N-(2- phenoxyethyl)-5,6,7,8-tetrahydroquinoline- 5-carboxamide

229

(5S,8S)-N- (4,6-dichloro-2,3- dihydrobenzofuran- 3-yl)-5-fluoro-8-hydroxy-5,6,7,8- tetrahydroquinoline- 5-carboxamide

230

(5S,8S)-N-(5,7- dichlorochroman- 4-yl)-5-fluoro- 8-hydroxy-5,6,7,8-tetrahydroquinoline- 5-carboxamide

231

(5S,8S)-N-(1- (adamantan-1-yl) ethyl)-5-fluoro-8- hydroxy-5,6,7,8-tetrahydroquinoline- 5-carboxamide

232

(5S,8S)-N-(2-(4- chlorophenyl)-2-(4,4- difluoropiperidin-1-yl)ethyl)-5-fluoro- 8-hydroxy-5,6,7,8- tetrahydroquinoline-5-carboxamide

233

(5S,8S)-N- (chroman-3- yl)-5-fluoro-8- hydroxy-5,6,7,8-tetrahydroquinoline- 5-carboxamide

234

(5S,8S)-N-(2-(4- chlorophenyl)propyl)- 5-fluoro-8-hydroxy- 5,6,7,8-tetrahydroquinoline- 5-carboxamide

235

(5S,8S)-5-fluoro-8- hydroxy-N-((rac)-2- morpholino-2-phenylethyl)-5,6,7,8- tetrahydroquinoline- 5-carboxamide

236

(5S,8S)-N-(2-(4,4- difluoropiperidin-1- yl)-2-(4- methylthiazol-5-yl)ethyl)-5-fluoro- 8-hydroxy-5,6,7,8- tetrahydroquinoline-5-carboxamide

237

(5S,8S)-N-((R)-1-(2- chloro-4-fluorophenyl) ethyl)-5-fluoro-8-hydroxy-5,6,7,8- tetrahydroquinoline- 5-carboxamide

238

(5S,8S)-N-((trans)-2- (2,4-dichlorophenyl) cyclopropyl)-5-fluoro-8-hydroxy-5,6,7,8- tetrahydroquinoline- 5-carboxamide

239

(5S,8S)-N-((S)-1-(2- chloro-4-fluorophenyl) ethyl)-5-fluoro-8-hydroxy-5,6,7,8- tetrahydroquinoline- 5-carboxamide

240

(5S,8S)-N-((4-(2,4- dichlorophenyl) tetrahydro-2H-pyran- 4-yl)methyl)-5-fluoro-8- hydroxy-5,6,7,8- tetrahydroquinoline- 5-carboxamide

241

(5S,8S)-N-(2,4- dichlorobenzyl)-3,5- difluoro-8-hydroxy- 5,6,7,8-tetrahydroquinoline- 5-carboxamide

242

(5S,8S)-N- (2-chloro-4- fluorobenzyl)-3,5- difluoro-8-hydroxy- 5,6,7,8-tetrahydroquinoline- 5-carboxamide

243

(5S,8S)-N-(2,4- dichlorobenzyl)-5- fluoro-8-hydroxy-3- methyl-5,6,7,8-tetrahydroquinoline- 5-carboxamide

244

(5S,8S)-N- (2-chloro-4- fluorobenzyl)-5- fluoro-8-hydroxy-3-methyl-5,6,7,8- tetrahydroquinoline- 5-carboxamide

TABLE 39-1 LC MS Examples Method tR (min) [M + H]⁺ 127 A 1.59 383.0 128A 1.50 403.1 129 A 1.50 403.1 132 A 1.49 369.1 133 A 1.49 369.1 134 A1.38 353.1 135 A 1.38 353.1 136 C 1.34 355.0 137 B 1.27 355.1 138 A 1.41369.1 139 A 1.41 369.1 140 C 1.29 337.1 141 B 1.22 337.1 142 A 1.45367.2 143 C 1.45 387.0 144 A 1.45 387.0 145 C 1.40 353.0 146 A 1.40353.0 147 A 1.60 437.1 148 A 1.60 437.0 149 A 1.58 419.1 150 D 1.26383.1 151 C 1.48 386.9 152 B 1.41 387.0 153 A 1.52 413.0 154 A 1.52413.0 155 A 1.56 383.2 156 C 1.55 403.0 157 B 1.49 403.0 158 A 1.45369.1 159 A 1.46 369.1 160 A 1.44 349.2 161 A 1.44 349.2 162 A 1.41371.2 163 A 1.41 371.2 164 A 1.51 403.1 165 A 1.52 403.0 166 A 1.46349.2 167 A 1.46 349.2 168 A 1.64 417.1 169 A 1.36 353.2 170 A 1.35371.2 171 A 1.34 353.1 172 A 1.38 365.2 173 A 1.45 369.1 174 B 1.34370.9 175 A 1.44 387.0 176 C 1.37 370.9 177 B 1.29 370.0 178 C 1.42387.1 179 A 1.46 403.0 180 B 1.22 355.1 181 A 1.48 413.0 182 B 1.35397.0 183 C 1.42 370.9 184 C 1.40 370.9 185 C 1.41 370.9 186 B 1.33387.0 187 A 1.45 387.0 188 B 1.31 353.1 189 C 1.46 341.1 190 A 1.37353.1 191 B 1.46 383.0 192 C 1.44 392.2 193 B 1.30 371.0 194 C 1.43404.0 195 A 1.34 335.0 196 C 1.38 327.1 197 A 1.47 369.0 198 A 1.40365.2 199 B 1.35 369.1 200 C 1.35 355.1 201 B 1.12 344.1 202 A 1.30337.1 203 B 1.33 353.1 204 A 1.36 353.2 205 A 1.35 335.1 206 B 1.32353.1 207 B 1.43 403.0 208 A 1.28 337.1 209 A 1.50 403.1 210 B 1.29335.1 211 B 1.39 399.1 212 B 1.43 369.0 213 C 1.52 418.0 214 C 1.36400.1 215 C 1.35 327.1 216 A 1.45 367.2 217 B 1.18 337.1 218 C 1.46341.1 219 C 1.48 399.1 220 C 1.44 359.1 221 B 1.23 337.1 222 C 1.35327.1 223 B 1.18 319.1 224 B 1.24 365.0 225 C 1.48 385.2 226 C 1.38327.1 227 C 1.40 295.2 228 C 1.29 331.1 229 C 1.49 397.1 230 C 1.55411.0 231 C 1.78 373.2 232 D 1.69 468.1 233 C 1.34 343.1 234 C 1.48363.1 235 C 1.23 400.2 236 D 1.30 455.2 237 D 1.50 367.1 238 D 1.68395.1 239 D 1.51 367.1 240 D 1.57 453.1 241 C 1.56 387.0 242 C 1.45371.1 243 D 1.67 383.1 244 D 1.54 367.1

Ex 126

¹H NMR (CDCl₃) delta 8.59 (1 H, d, J 4.6 HL), 7.53 (1H, d, J=7.9 HL),7.31 (1H, br s), 7.25 (1H, m), 7.14 (1 H, br s), 6.98 (1H, br d, J=5.3Hz), 4.80 (1H, dd, J=5.3, 5.3 Hz), 4.70 (1H, dd, J=13.8, 5.9 Hz), 4.60(1H, dd, J=13.8, 5.9 Hz), 3.79 (1H, br s), 2.65 (1H, m), 2.46 (3 H, s),2.40-2.28 (2 H, m), 2.16 (1H, m).

MS (ESI) m/z: 382.9 (M+H)⁺.

Chiral HPLC tR: 13.6 min (Method I), 99.0% e.e., >99% d.e.

Ex 127

¹H NMR was identified with the Example 126.

Chiral HPLC tR: 17.0 min (Method I), 98.2% e.e., >99% d.e. Ex 128

¹H NMR (CDCl₃) delta 8.58 (1H, ddd, J=4.6, 2.0, 1.3 Hz), 7.70 (1H, d,J=7.9 Hz), 7.64 (1H, d, J=7.2 Hz), 7.54 (1H, d, J=7.9 Hz), 7.39 (1H, dd,J=7.9, 7.2 Hz), 7.24 (1 H, br), 7.23 (1H, dd, J=7.9, 4.6 Hz), 4.81 (1H,dd, J=5.3, 4.6 Hz), 4.71 (2 H, d, J=5.9 Hz), 3.87 (1 H, br), 2.68 (1H,m), 2.42-2.08 (3H, m).

Chiral HPLC tR: 35.1 min (Method K), >99% e.e., d.e.

Ex 129

¹H NMR was identified with the Example 128.

Chiral HPLC tR: 23.9 min (Method K), >99% e.e., d.e.

Ex 130

¹H NMR (DMSO d6) delta 8.69 (1 H, br), 8.61 (1H, d, J=4.6 Hz), 7.56 (1H,d, J=2.0 Hz), 7.55 (1H, d, J=7.9 Hz), 7.48 (1H, d, J=2.0 Hz), 7.38 (1H,dd, J=7.9, 4.6 Hz), 5.54 (1H, t, J=5.3 Hz), 5.43 (1H, d, J=4.0 Hz), 4.70(2H, d, J=5.3 Hz), 4.63 (1H, d, J=4.0 Hz), 4.50 (2H, m), 2.76-2.55 (1H,m), 2.14-1.90 (3H, m). MS (ESI) m/z: 398.9 (M+H)⁺.

Chiral HPLC tR: 14.1 min (Method J), 98.2% e.e., >99% d.e.

Ex 131

¹H NMR and MS were identified with the Example 130.

Chiral HPLC tR: 39.1 min (Method J), >99% e.e., d.e.

Ex 132

¹H NMR (CDCl₃) delta 8.59 (1H, ddd, J=4.9, 1.8, 1.2 Hz), 7.54 (1H, dd,J=7.9, 1.2 Hz), 7.45 (1H, d, J=1.8 Hz), 7.36 (1H, d, J=7.9 Hz),7.31-7.23 (2H, m), 7.18 (1 H, br), 4.80 (1H, ddd, J=6.7, 6.0, 1.2 Hz),4.63 (1H, dd, J=14.7, 6.1 Hz), 4.57 (1H, dd, J=14.7, 6.1 Hz), 3.79 (1 H,br s), 2.67 (1H, m), 2.41-2.25 (2H, m), 2.15 (1H, m).

Ex 133

¹H NMR was identified with the Example 132.

Ex 134

¹H NMR (CDCl₃) delta 8.60 (1H, ddd, J=4.9, 1.8, 1.2 Hz), 7.54 (1H, ddd,J=7.9, 1.8, 1.2 Hz), 7.41 (1H, dd, J=8.6, 6.1 Hz), 7.25 (1H, dd, J=7.9,4.9 Hz), 7.19 (1H, dd, J=7.9, 2.4 Hz), 7.13 (1H, br d, J=5.5 Hz), 7.00(1H, ddd, J=8.6, 7.9, 2.4 Hz), 4.81 (1H, dd, J=5.5, 4.9 Hz), 4.63 (1H,dd, J=14.7, 6.1 Hz), 4.57 (1H, dd, J=14.7, 5.5 Hz), 3.74 (1 H, br s),2.67 (1H, m), 2.41-2.25 (2H, m), 2.15 (1H, m).

Ex 135

¹H NMR was identified with the Example 134.

Ex 150

¹H NMR (CDCl₃) delta 8.58 (1H, ddd, J=4.9, 1.8, 1.2 Hz), 7.52 (1H, br d,J=4.9 Hz), 7.48 (1H, ddd, J=7.9, 1.8, 1.2 Hz), 7.23 (1H, dd, J=7.9, 4.9Hz), 7.17 (1H, dd, J=7.9, 2.4 Hz), 7.09 (1H, dd, J=8.6, 2.4 Hz),4.79-4.73 (4H, m), 4.65 (1H, dd, J=14.7, 6.1 Hz), 3.82 (1 H, br), 3.67(1 H, br), 2.61 (1H, m), 2.37-2.21 (2H, m), 2.11 (1 H, m).

Ex 158

¹H NMR (CDCl₃) delta 8.61 (1 H, br dd, J=4.9, 1.6 Hz), 7.56 (1H, d,J=7.9 Hz), 7.41 (1H, dd, J=7.9, 1.6 Hz), 7.34 (1H, dd, J=7.6, 1.3 Hz),7.28-7.15 (3H, m), 4.81 (1H, dd, J=6.3, 4.9 Hz), 4.70 (1H, dd, J=14.5,5.9 Hz), 4.63 (1H, dd, J=14.5, 6.3 Hz), 3.62 (1 H, s), 2.66 (1H, m),2.44-2.08 (3H, m).

Ex 159

¹H NMR was identified with the Example 158.

Ex 191

¹H NMR (CDCl₃) delta 8.58 (1H, m), 7.42 (1H, d, J=1.8 Hz), 7.39 (1H, d,J=7.9 Hz), 7.25-7.20 (2H, m), 7.19 (1H, d, J=7.9 Hz), 6.79 (1 H, br),4.80 (1H, ddd, J=6.4, 5.2, 1.2 Hz), 3.80 (1 H, br), 3.75-3.59 (2H, m),3.03 (2 H, dt, J=6.7, 1.8 Hz), 2.62 (1H, m), 2.38-2.22 (2H, m), 2.10(1H, m).

Ex 192

¹H NMR (CDCl₃) delta 8.61 (1H, br d, J=4.9 Hz), 7.60 (1H, d, J=7.9 Hz),7.28 (2 H, dd, J=7.9, 4.9 Hz),4.83 (1H, dd, J=6.1, 5.5 Hz), 3.76 (1H,br), 3.69 (4H, dd, J=4.9, 4.3 Hz), 3.48 (1H, dd, J=14.1, 6.1 Hz), 3.41(1H, dd, J=14.1, 5.5 Hz), 2.70 (1 H, m), 2.63 (4H, dd, J=4.9, 4.3 Hz),2.38 (1H, m), 2.28 (1H, m), 2.16 (1H, m), 1.70-1.52 (5H, m), 1.47-1.37(4H, m), 1.24 (1H, m).

Ex 237

¹H NMR (CDCl₃) delta 8.56 (1 H, br dd, J=4.3, 1.8 Hz), 7.50 (1 H, br dd,J=7.9, 1.8 Hz), 7.39 (1H, dd, J=8.6, 6.1 Hz), 7.21 (1H, dd, J=7.9, 4.3Hz), 7.16 (1 H, dd, J=7.9, 3.1 Hz), 7.08 (1H, m), 7.02 (1H, ddd, J=8.6,7.9, 3.1 Hz), 5.43 (1H, m), 4.81 (1 H, br t, J=5.8 Hz), 2.90 (1 H, br),2.69 (1H, m), 2.41-2.26 (2H, m), 2.17 (1H, m), 1.60 (3H, d, J=7.3 Hz).

Ex 238

¹H NMR (CDCl₃) delta 8.63 (1H, m), 7.62 (1H, br d, J=7.3 Hz), 7.40 (0.5H, d, J=1.8 Hz), 7.39 (0.5 H, d, J=1.8 Hz), 7.30 (0.5 H, dd, J=7.9, 4.3Hz), 7.29 (0.5 H, dd, J=7.9, 4.3 Hz), 7.180 (0.5 H, dd, J=8.6, 1.8 Hz),7.179 (0.5 H, dd, J=8.6, 1.8 Hz), 7.12 (0.5 H, d, J=8.6 Hz), 7.11 (0.5H, d, J=8.6 Hz), 6.98 (1 H, br), 4.82 (1 H, br), 3.68 (1 H, br), 3.05(1H, m), 2.69 (1H, m), 2.42-2.25 (3H, m), 2.17 (1H, m), 1.41-1.24 (2H,m).

Ex 239

¹H NMR (CDCl₃) delta 8.61 (1 H, br dd, J=4.9, 1.8 Hz), 7.65 (1 H, br dd,J=7.9, 1.8 Hz), 7.35 (1H, dd, J=8.6, 6.1 Hz), 7.30 (1H, dd, J=7.9, 4.9Hz), 7.16 (1 H, dd, J=8.6, 2.4 Hz), 7.08 (1H, br), 7.02 (1H, ddd, J=8.6,6.1, 2.4 Hz), 5.41 (1H, m), 4.80 (1 H, br), 3.75 (1 H, br), 2.60 (1H,m), 2.37-2.07 (3H, m), 1.60 (3H, d, J=7.3 Hz).

Ex 240

¹H NMR (CDCl₃) delta 8.58 (1 H, br dd, J=4.9, 1.8 Hz), 7.47 (1H, d,J=1.8 Hz), 7.33 (1H, dd, J=8.6, 1.8 Hz), 7.29 (1H, d, J=8.6 Hz), 7.21(1H, dd, J=7.9, 4.9 Hz), 7.15 (1H, br d, J=7.9 Hz), 6.32 (1 H, br), 4.75(1 H, br dd, J=5.5, 4.9 Hz), 4.18 (1H, dd, J=14.1, 6.1 Hz), 3.95 (1H,dd, J=14.1, 6.1 Hz), 3.92-3.83 (2H, m), 3.74-3.55 (3H, m), 2.49 (1H, m),2.40-2.55 (3H, m), 2.24-2.08 (3H, m), 2.01 (1H, m).

TABLE 40 Inter- mediates Structure Chemical Name Substrate Amine I-d-1

(5S,8S)-N-((R)-1-(2,4- dichlorophenyl)ethyl)-5-fluoro-8-hydroxy-5,6,7,8- tetrahydroquinoline-5- carboxamide

I-d-2

(5S,8S)-N-(2,3-dichloro- 4-fluorobenzyl)-5- fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5- carboxamide

I-d-3

(5S,8S)-N-(2,4-dichloro- 3-fluorobenzyl)-5-fluoro- 8-hydroxy-5,6,7,8-tetrahydroquinoline-5- carboxamide

I-d-4

(5S,8S)-N-(2-chloro-4- (trifluoromethyl)benzyl)- 5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline- 5-carboxamide

I-d-5

(5S,8S)-N-((S)-1-(2,4- dichlorophenyl)ethyl)-5-fluoro-8-hydroxy-5,6,7,8- tetrahydroquinoline-5- carboxamide

IM I-d-1

MS (ESI) m/z: 383.2 (M+H)⁺.

IM I-d-2

MS (ESI) m/z: 386.9 (M+H)⁺.

IM I-d-3

MS (ESI) m/z: 386.9 (M+H)⁺.

IM I-d-4

MS (ESI) m/z: 403.0 (M+H)⁺.

IM I-d-5

MS (ESI) m/z: 383.2 (M+H)⁺.

Intermediate (IM) I-d-6:

(5S,8S)-N-(2-(((tert-butyldimethylsilyl)oxy)methyl)-6-chloro-4-fluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide

To a solution of(5S,8S)-N-(2-chloro-4-fluoro-6-(hydroxymethyl)benzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide(174 mg, 0.455 mmol, Ex 150) in CH₂Cl₂ (1.0 mL) was added imidazole (93mg, 1.364 mmol) at 0° C. After 10 min stirring, TBSCl (82 mg, 0.545mmol) was added to the mixture at 0° C. Then the mixture was allowed towarm to room temperature and stirred for 3 h. The mixture was dilutedwith cold water and extracted with CH₂Cl₂. The extracts were washed withbrine, dried over Na₂ SO₄, and then concentrated in vacuo. The resultingresidue was purified by silica gel column chromatography (30- to 100%EtOAc/n-hexane, gradient) to afford 165 mg (73%) of the title compound.

IM I-d-6

¹H NMR (CDCl₃) delta 8.58 (1H, br d, J=4.9 Hz), 7.55 (1H, br d, J=7.9Hz), 7.24 (1H, dd, J=7.9, 4.9 Hz), 7.15 (1H, dd, J=9.8, 3.1 Hz), 7.12(1H, dd, J=8.6, 3.1 Hz), 7.05 (1H, br d, J=5.5 Hz), 4.89 (1H, d, J=13.4Hz), 4.82 (1H, d, J=13.4 Hz), 4.80 (1H, m), 4.70 (1H, dd, J=14.1, 6.1Hz), 4.57 (1H, dd, J=14.1, 5.5 Hz), 3.80 (1 H, br), 2.66 (1H, m),2.39-2.25 (2H, m), 2.12 (1H, m), 0.94 (9H, s), 0.12 (3H, s), 0.11 (3 H,s).

MS (ESI) m/z: 496.8 (M+H)⁺.

Example 245(5S,8S)-5-((2,4-dichlorobenzyl)carbamoyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline1-oxide

To a stirred solution of(5S,8S)-N-(2,4-dichlorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide (30 mg, 0.081 mmol, Ex 133) in CH₂Cl₂ (2 mL) was added mCPBA (17mg, 0.099 mmol) at 0° C. The mixture was stirred at 0° C. for 2 h, andthen warmed to room temperature. After being stirred at room temperaturefor 16 h, aq. Na₂S₂O₃ was added to the mixture. The resulting mixturewas stirred for 30 min vigorously, and then extracted with EtOAc. Theextract was washed with aq. NaHCO₃, water, and brine. The extract wasdried over Na₂SO₄ and concentrated in vacuo. The resulting solid waswashed with EtOAc to afford 22 mg (70%) of the title compound.

Ex 245

¹H NMR (CDCl₃) delta 8.27 (1H, ddd, J=4.9, 1.8, 1.2 Hz), 7.46 (1H, d,J=1.8 Hz), 7.38 (1H, d, J=7.9 Hz), 7.28-7.25 (2H, m), 7.16-7.14 (2H, m),5.23 (1 H, br), 5.15 (1 H, br), 4.65 (1H, dd, J=14.7, 6.1 Hz), 4.59 (1H,dd, J=14.7, 6.1 Hz), 2.61 (1 H, m), 2.33-2.28 (2H, m), 2.11 (1H, m).

LCMS (ESI) m/z: 385.0 (M+H)⁺, tR 1.40 min (Method D).

Intermediate (IM) II-e-2-6:

(5R)-Methyl5-fluoro-8-methylene-5,6,7,8-tetrahydroquinoline-5-carboxylate

Intermediate (IM) II-e-2-7:

(5S)-Methyl5-fluoro-8-methylene-5,6,7,8-tetrahydroquinoline-5-carboxylate

The title compounds were prepared by chiral HPLC separation of methyl5-fluoro-8-methylene-5,6,7,8-tetrahydroquinoline-5-carboxylate (IMII-e-2-1).

IM II-e-2-6 Chiral HPLC tR: 15.1m (Method L),>98% e.e.

IM II-e-2-7

Chiral HPLC tR: 17.8m (Method L),>98% e.e.

The following Intermediates were prepared by General Procedure A (Table41), except Intermediate I-e-35.

The Intermediate I-e-35 was prepared by General Procedure N (Table 41).

TABLE 41 Inter- mediates Structure Chemical Name Substrate Amine I-e-25

(R)-N-(2-chloro-3- (trifluoromethyl)benzyl)- 5-fluoro-8-methylene-5,6,7,8-tetrahydro- quinoline-5-carboxamide

I-e-26

(R)-N-(2,4-dichlorobenzyl)- 5-fluoro-8-methylene- 5,6,7,8-tetrahydro-quinoline-5-carboxamide

I-e-27

(S)-N-(2-chloro-3- (trifluoromethyl)benzyl)- 5-fluoro-8-methylene-5,6,7,8-tetrahydro- quinoline-5-carboxamide

I-e-28

(S)-N-(2,4-dichlorobenzyl)- 5-fluoro-8-methylene- 5,6,7,8-tetrahydro-quinoline-5-carboxamide

I-e-29

(S)-N-(2,4-dichloro-6- fluorobenzyl)-5-fluoro-8- methylene-5,6,7,8-tetrahydroquinoline-5- carboxamide

I-e-30

(S)-N-(2-chloro-3,4- difluorobenzyl)-5-fluoro- 8-methylene-5,6,7,8-tetrahydroquinoline-5- carboxamide

I-e-31

(S)-N-(2-chloro-4-fluoro benzyl)-5-fluoro-8- methylene-5,6,7,8-tetrahydroquinoline-5- carboxamide

I-e-32

(S)-N-(4-chloro-2-fluoro benzyl)-5-fluoro-8- methylene-5,6,7,8-tetrahydroquinoline-5- carboxamide

I-e-33

(S)-5-fluoro-8-methylene- N-(2,3,4-trifluorobenzyl)- 5,6,7,8-tetrahydro-quinoline-5-carboxamide

I-e-34

(S)-N-(2,3-dichlorobenzyl)- 5-fluoro-8-methylene- 5,6,7,8-tetrahydro-quinoline-5-carboxamide

I-e-35

(S)-N-(2,4-dichloro-6- (hydroxymethyl)benzyl)-5- fluoro-8-methylene-5,6,7,8-tetrahydro- quinoline-5-carboxamide

IM I-e-25

¹H NMR and MS were identified with the IM I-e-3.

IM I-e-26

¹H NMR and MS were identified with the IM I-e-19.

IM I-e-27

¹H NMR and MS were identified with the IM I-e-3.

IM I-e-28

¹H NMR and MS were identified with the IM I-e-19.

IM I-e-29

MS (ESI) m/z: 384.6 (M+H)⁺.

IM I-e-30

¹H NMR (CDCl₃) delta 8.61 (1 H, br dd, J=4.3, 1.8 Hz), 7.48 (1 H, br dd,J=7.9, 1.8 Hz), 7.24 (1 H, br), 7.24-7.17 (2H, m), 7.10 (1H, m), 6.35(1H, s), 5.31 (1H, s), 4.66 (1H, dd, J=15.3, 6.1 Hz), 4.62 (1H, dd,J=15.3, 6.1 Hz), 2.88-2.82 (2H, m), 2.47 (1H, m), 2.27 (1H, m).

MS (ESI) m/z: 367.1 (M+H)⁺.

IM I-e-31

¹H NMR and MS were identified with the IM I-e-20.

IM I-e-32

MS (ESI) m/z: 348.8 (M+H)⁺.

IM I-e-33

¹H NMR (CDCl₃) delta 8.61 (1 H, br dd, J=4.9, 1.8 Hz), 7.46 (1 H, br dd,J=7.9, 1.8 Hz), 7.21-7.10 (3H, m), 6.98 (1H, m), 6.36 (1H, s), 5.31 (1H,s), 4.63 (1 H, dd, J=14.7, 6.1 Hz), 4.58 (1H, dd, J=14.7, 6.1 Hz),2.90-2.79 (2H, m), 2.47 (1H, m), 2.26 (1H, m).

MS (ESI) m/z: 350.8 (M+H)⁺.

IM I-e-34

¹H NMR and MS were identified with the IM I-e-18.

IM I-e-35

¹H NMR and MS were identified with the IM I-e-17.

The following Examples and Intermediates were prepared by GeneralProcedure B or O (Tables 42 and 44).

General Procedure O

To a solution of substrate (1.0 eq.) in CH₂Cl₂ was added Dess-MartinPeriodinane (1.5 eq.) at ambient temperature. After being stirred untilcomplete reaction, aq. Na₂S₂ O₃ and aq. NaHCO₃ were added to themixture. The mixture was extracted with CH₂Cl₂ and washed with water.The extract was dried over Na₂SO₄ and concentrated in vacuo to afford asolid. The residual solid was purified by silica gel columnchromatography and preparative HPLC to afford following Examples andIntermediates.

TABLE 42 Ex- General amples Structure Chemical Name Substrate Procedure246

(R)-N-(2-chloro-3- (trifluoromethyl) benzyl)-5- fluoro-8-oxo-5,6,7,8-tetrahydroquinoline-5- carboxamide

B 247

(S)-N-(2-chloro-3- (trifluoromethyl) benzyl)-5- fluoro-8-oxo-5,6,7,8-tetrahydroquinoline-5- carboxamide

B 248

(S)-N-(2,4-dichloro- benzyl)- 5-fluoro-8-oxo-5,6,7,8-tetrahydroquinoline-5- carboxamide

B 249

(S)-N-(2-chloro-4-fluoro benzyl)-5-fluoro-8-oxo- 5,6,7,8-tetra-hydroquinoline-5- carboxamide

O 250

(S)-N-(2-chloro-3-fluoro benzyl)-5-fluoro-8-oxo- 5,6,7,8-tetrahydro-quinoline-5-carboxamide

O 251

(S)-N-(2,4-dichloro-6- fluorobenzyl)-5-fluoro-8- oxo-5,6,7,8-tetrahydro-quinoline-5-carboxamide

O 252

(S)-N-(2,3-dichloro- benzyl)- 5-fluoro-8-oxo-5,6,7,8-tetrahydroquinoline-5- carboxamide

B 253

(S)-N-(2-chloro-4- (trifluoromethyl) benzyl)-5- fluoro-8-oxo-5,6,7,8-tetrahydroquinoline-5- carboxamide

O 254

(S)-5-fluoro-8-oxo-N- (2,3,4-trifluorobenzyl)- 5,6,7,8-tetrahydro-quinoline-5-carboxamide

O 255

(S)-N-((3,5-dichloro- pyridin-2-yl)methyl)-5- fluoro-8-oxo-5,6,7,8-tetrahydroquinoline-5- carboxamide

O

TABLE 43 LC MS Examples Method tR (min) [M + H]⁺ 246 A 1.51 401.1 247 A1.51 401.1 248 B 1.44 367.0 249 B 1.33 351.0 250 B 1.31 351.0 251 B 1.44384.9 252 B 1.40 366.9 253 B 1.49 400.9 254 C 1.35 353.0 255 D 1.43368.0

Ex 246

¹H NMR was identified with the Example 13.

Ex 247

¹H NMR was identified with the Example 13.

Ex 248

¹H NMR (DMSO d6) delta 9.35 (1 H, br), 8.85 (1H, d, J=4.9 Hz), 7.95 (1H,dd, J=7.9, 1.8 Hz), 7.73 (1H, dd, J=7.9, 4.9 Hz), 7.62 (1H, d, J=1.8Hz), 7.44 (1 H, dd, J=7.9, 1.8 Hz), 7.34 (1H, d, J=7.9 Hz), 4.44 (1H,dd, J=15.9, 6.1 Hz), 4.39 (1H, dd, J=15.9, 5.5 Hz), 2.89-2.85 (2H, m),2.77-2.58 (2H, m).

Ex 249

¹H NMR (DMSO d6) delta 9.31 (1 H, br), 8.85 (1H, dd, J=4.9, 1.8 Hz),7.95 (1H, dd, J=7.9, 1.8 Hz), 7.73 (1H, dd, J=7.9, 4.9 Hz), 7.45 (1H,dd, J=8.6, 3.1 Hz), 7.38 (1H, dd, J=8.6, 6.1 Hz), 7.23 (1H, ddd, J=8.6,8.6, 3.1 Hz),4.44 (1H, dd, J=15.9, 6.1 Hz), 4.39 (1H, dd, J=15.9, 5.5Hz), 2.94-2.81 (2H, m), 2.77-2.54 (2H, m).

Ex 252

¹H NMR (CDCl₃) delta 8.90 (1H, dd, J=4.6, 1.3 Hz), 7.75 (1H, dd, J=7.9,1.3 Hz),7.52 (1H, dd, J=7.9, 4.6 Hz), 7.48 (1H, dd, J=7.9, 2.0 Hz), 7.33(1H, dd, J=7.9, 2.0 Hz), 7.23-7.20 (1 H, br), 7.22 (1H, dd, J=7.9, 7.9Hz), 4.68 (2H, d, J=5.9 Hz), 3.17 (1H, m), 3.02 (1H, m), 2.81 (1H, m),2.58 (1H, m).

Ex 253

¹H NMR (DMSO d6) delta 9.35 (1 H, br), 8.84 (1H, d, J=4.3 Hz), 7.90 (1H,dd, J=7.9, 1.2 Hz), 7.71 (1H, dd, J=7.9, 4.3 Hz), 7.29 (1H, m), 7.19(1H, m), 4.43 (1H, dd, J=15.3, 5.5 Hz), 4.39 (1H, dd, J=15.3, 5.5 Hz),2.88-2.84 (2H, m), 2.73-2.56 (2 H, m).

TABLE 44 General Inter- Pro- mediates Structure Chemical Name Substratecedure I-c-13

(S)-N-(4-chloro- 2-fluoro benzyl)-5-fluoro- 8-oxo- 5,6,7,8- tetrahydro-quinoline- 5-carboxamide

O I-c-14

(S)-N-(2,3- dichloro-4- fluorobenzyl)- 5-fluoro-8- oxo-5,6,7,8-tetrahydro- quinoline-5- carboxamide

O I-c-15

(S)-N-(4- chloro-2,3- difluorobenzyl)- 5-fluoro-8- oxo-5,6,7,8-tetrahydro- quinoline-5- carboxamide

O I-c-16

(S)-N-(2,4- dichloro-3- fluorobenzyl)- 5-fluoro-8- oxo-5,6,7,8-tetrahydro- quinoline-5- carboxamide

O I-c-17

(S)-N-(2,4- difluorobenzyl)- 5-fluoro-8- oxo-5,6,7,8- tetrahydro-quinoline- 5-carboxamide

O I-c-18

(S)-N-(3- chloro-2,4- difluorobenzyl)- 5-fluoro-8- oxo-5,6,7,8-tetrahydro- quinoline-5- carboxamide

O I-c-19

(S)-N-(4-chloro- 2,6- difluorobenzyl)- 5-fluoro-8- oxo-5,6,7,8-tetrahydro- quinoline-5- carboxamide

O I-c-20

(S)-N-(2- chloro-4,6- difluorobenzyl)- 5-fluoro-8- oxo-5,6,7,8-tetrahydro- quinoline-5- carboxamide

O I-c-21

(S)-N-(2,4- dichloro-6- (hydroxymethyl) benzyl)-5- fluoro-8-oxo-5,6,7,8- tetrahydro- quinoline-5- carboxamide

B I-c-22

(S)-N-(2- (((tert-butyl- dimethylsilyl) oxy)methyl)- 6-chloro-4-fluorobenzyl)- 5-fluoro-8-oxo- 5,6,7,8- tetrahydro- quinoline-5-carboxamide

O I-c-23

(S)-N-((R)-1- (2,4-dichloro- phenyl)ethyl)- 5-fluoro- 8-oxo-5,6,7,8-tetrahydro- quinoline-5- carboxamide

O I-c-24

(S)-N-((S)-1- (2,4-dichloro- phenyl)ethyl)- 5-fluoro-8- oxo-5,6,7,8-tetrahydro- quinoline- 5-carboxamide

O I-c-25

(S)-N-((R)- 1-(2-chloro-4- fluorophenyl) ethyl)-5- fluoro-8-oxo-5,6,7,8- tetrahydro- quinoline-5- carboxamide

O I-c-26

(S)-N-((S)-1- (2-chloro-4- fluorophenyl) ethyl)-5- fluoro-8-oxo-5,6,7,8- tetrahydro- quinoline-5- carboxamide

O I-c-27

(S)-N-(2,4- dichloro- phenethyl)-5- fluoro-8-oxo- 5,6,7,8- tetrahydro-quinoline- 5-carboxamide

O I-c-28

(S)-N-((trans)- 2-(2,4-dichloro- phenyl)cyclo- propyl)-5-fluoro-8-oxo-5,6,7,8- tetrahydro- quinoline- 5-carboxamide

O I-c-29

(S)-5-fluoro- N-((1- morpholino- cyclohexyl) methyl)-8- oxo-5,6,7,8-tetrahydro- quinoline-5- carboxamide

O I-c-30

(S)-N-((4- (2,4-dichloro- phenyl)tetra- hydro-2H- pyran-4-yl) methyl)-5-fluoro-8- oxo-5,6,7,8- tetrahydro- quinoline-5- carboxamide

O I-c-31

(S)-N-(2,4- dichloro- benzyl)- 5-fluoro- 3-methyl- 8-oxo-5,6,7,8-tetrahydro- quinoline-5- carboxamide

O I-c-32

(S)-N-(2- chloro-4-fluoro benzyl)-5- fluoro-3- methyl-8- oxo-5,6,7,8-tetrahydro- quinoline-5- carboxamide

O

IM II-c-13

MS (ESI) m/z: 350.8 (M+H)⁺.

IM II-c-14

MS (ESI) m/z: 384.8 (M+H)⁺.

IM II-c-15

MS (ESI) m/z: 368.8 (M+H)⁺.

IM II-c-16

MS (ESI) m/z: 384.8 (M+H)⁺.

IM II-c-17

MS (ESI) m/z: 334.8 (M+H)⁺.

IM II-c-18

MS (ESI) m/z: 368.8 (M+H)⁺.

IM I-c-19

MS (ESI) m/z: 368.8 (M+H)⁺.

IM I-c-20

MS (ESI) m/z: 368.8 (M+H)⁺.

IM I-c-21

¹H NMR and MS were identified with the Ex 14.

IM I-c-22

¹H NMR (CDCl₃) delta 8.88 (1H, ddd, J=4.3, 1.8, 1.2 Hz), 7.74 (1H, br d,J=7.9 Hz), 7.50 (1H, dd, J=7.9, 4.3 Hz), 7.14 (3H, br d, J=7.9 Hz), 4.88(1H, d, J=13.4 Hz), 4.82 (1H, d, J=13.4 Hz), 4.71 (1H, dd, J=14.1, 5.5Hz), 4.62 (1H, dd, J=14.1, 5.5 Hz), 3.16 (1H, m), 2.99 (1H, m), 2.79(1H, m), 2.54 (1H, m), 0.94 (9H, s), 0.12 (3H, s), 0.11 (3 H, s).

MS (ESI) m/z: 494.8 (M+H)⁺.

IM I-c-23

¹H NMR (CDCl₃) delta 8.87 (1H, ddd, J=4.3, 1.8, 1.2 Hz), 7.67 (1H, dd,J=7.9, 2.4 Hz), 7.48 (1H, dd, J=7.9, 4.3 Hz), 7.43 (1H, d, J=1.8 Hz),7.33 (1H, d, J=8.6 Hz), 7.29 (1H, dd, J=8.6, 2.4 Hz), 7.12 (1 H, br),5.42 (1H, m), 3.18 (1H, m), 3.02 (1H, m), 2.83 (1H, m), 2.59 (1H, m),1.62 (3H, d, J=6.7 Hz).

MS (ESI) m/z: 381.4 (M+H)⁺.

IM I-c-24

¹H NMR (DMSO d6) delta 9.34 (1H, br d, J=6.1 Hz), 8.85 (1H, br d, J=4.3Hz), 7.97 (1H, dd, J=7.9, 1.8 Hz), 7.74 (1H, dd, J=7.9, 4.9 Hz), 7.59(1H, d, J=1.8 Hz), 7.57 (1H, d, J=7.9 Hz), 7.48 (1H, dd, J=7.9, 1.8 Hz),5.23 (1H, m), 2.83 (1H, m), 2.74-2.50 (3H, m), 1.44 (3H, d, J=7.3 Hz).

MS (ESI) m/z: 381.0 (M+H)⁺.

IM I-c-25

¹H NMR (DMSO d6) delta 9.28 (1H, br d, J=7.3 Hz), 8.81 (1H, br d, J=4.3Hz), 7.84 (1H, dd, J=7.9, 1.8 Hz), 7.69 (1H, dd, J=7.9, 4.3 Hz), 7.59(1H, dd, J=8.6, 6.1 Hz), 7.37 (1H, dd, J=8.6, 2.4 Hz), 7.24 (1H, dt,J=8.6, 2.4 Hz),5.26 (1H, m), 2.98-2.80 (2H, m), 2.77-2.54 (2H, m), 1.43(3H, d, J=6.7 Hz).

MS (ESI) m/z: 365.0 (M+H)⁺.

IM I-c-26

¹H NMR (DMSO d6) delta 9.32 (1H, br d, J=7.3 Hz), 8.85 (1H, d, J=4.3Hz), 7.98 (1H, br d, J=7.9 Hz), 7.74 (1H, dd, J=7.9, 4.3 Hz), 7.60 (1H,dd, J=8.6, 6.1 Hz), 7.40 (1H, br d, J=9.2 Hz), 7.28 (1 H, dt, J=8.6, 2.4Hz), 5.26 (1H, m), 2.83 (1 H, m), 2.76-2.51 (3H, m), 1.44 (3H, d, J=7.3Hz).

MS (ESI) m/z: 365.0 (M+H)⁺.

IM T-c-27

¹H NMR (CDCl₃) delta 8.88 (1H, br d, J=4.3 Hz), 7.57 (1H, d, J=7.9 Hz),7.49 (1 H, dd, J=7.9, 4.3 Hz), 7.43 (1H, d, J=1.8 Hz), 7.23 (1H, dd,J=7.9, 1.8 Hz), 7.18 (1H, d, J=7.9 Hz), 6.85 (1 H, br), 3.77-3.62 (2H,m), 3.17-2.94 (4H, m), 2.74 (1H, m), 2.52 (1H, m).

MS (ESI) m/z: 381.0 (M+H)⁺.

IM I-c-28

¹H NMR (CDCl₃) delta 8.91 (1H, m), 7.81 (1H, dd, J=7.9, 1.8 Hz),7.57-7.53 (1H, m), 7.403 (0.5 H, d, J=2.4 Hz), 7.397 (0.5 H, d, J=2.4Hz), 7.189 (0.5 H, dd, J=8.6, 1.8 Hz), 7.185 (0.5 H, dd, J=8.6, 1.8 Hz),7.09 (0.5 H, d, J=8.6 Hz), 7.08 (0.5 H, d, J=8.6 Hz), 7.06 (1 H, br),3.23-3.14 (1H, m), 3.10-2.96 (2H, m), 2.89-2.76 (1H, m), 2.64-2.54 (1H,m), 2.36-2.29 (1H, m), 1.44-1.30 (2H, m).

MS (ESI) m/z: 393.3 (M+H)⁺.

IM I-c-29

¹H NMR (CDCl₃) delta 8.90 (1H, ddd, J=4.3, 1.8, 1.2 Hz), 7.77 (1H, dd,J=7.9, 1.2 Hz), 7.53 (1H, dd, J=7.9, 4.3 Hz), 7.46 (1 H, br), 3.73 (4H,dd, J=4.9, 4.3 Hz), 3.48 (1H, dd, J=13.8, 4.9 Hz), 3.45 (1H, dd, J=13.8,4.9 Hz), 3.17 (1H, m), 3.02 (1 H, m), 2.83 (1H, m), 2.66 (4H, dd, J=4.9,4.3 Hz), 2.57 (1H, m), 1.76-1.22 (10H, m).

MS (ESI) m/z: 390.4 (M+H)⁺.

IM I-c-30

¹H NMR (CDCl₃) delta 8.87 (1H, ddd, J=4.9, 1.8, 1.2 Hz), 7.48 (1H, d,J=1.8 Hz), 7.46 (1H, dd, J=7.9, 4.9 Hz), 7.35-7.32 (2H, m), 7.29 (1H, d,J=8.6 Hz), 6.40 (1 H, br d, J=6.1 Hz), 4.16 (1H, dd, J=14.1, 6.1 Hz),3.98 (1H, dd, J=14.1, 6.1 Hz), 3.92-3.83 (2H, m), 3.73-3.61 (2H, m),3.06 (1H, m), 2.93 (1H, m), 2.61 (1H, m), 2.47-2.36 (3H, m), 2.13-2.08(2H, m).

MS (ESI) m/z: 450.9 (M+H)⁺.

IM I-c-31

¹H NMR (CDCl₃) delta 8.68 (1 H, br s), 7.462 (1H, d, J=1.8 Hz), 7.456(1H, d, J=2.4 Hz), 7.37 (1H, d, J=7.9 Hz), 7.27 (1H, dd, J=7.9, 1.8 Hz),7.23 (1 H, br), 4.64 (1H, dd, J=15.3, 6.1 Hz), 4.61 (1H, dd, J=15.3, 6.1Hz), 3.11 (1H, m),2.97 (1H, m), 2.79 (1H, m), 2.54 (1H, m), 2.40 (3 H,s).

MS (ESI) m/z: 381.0 (M+H)⁺.

IM I-c-32

¹H NMR (CDCl₃) delta 8.69 (1 H, br s), 7.46 (1H, d, J=1.2 Hz), 7.42 (1H,dd, J=8.6, 6.1 Hz), 7.20 (1H, dd, J=7.9, 2.4 Hz), 7.20 (1 H, br), 7.01(1 H, dt, J=8.6, 2.4 Hz), 4.64 (1H, dd, J=14.7, 6.1 Hz), 4.61 (1H, dd,J=14.7, 6.1 Hz), 3.10 (1H, m), 2.97 (1H, m), 2.79 (1H, m), 2.54 (1H, m),2.40 (3 H, s).

MS (ESI) m/z: 365.2 (M+H)⁺.

The following Intermediates were prepared by General Procedure G or H(Table 45).

In the preparation of the Intermediate (IM) I-g-16, the TBS group wasremoved under this reaction condition.

TABLE 45 Inter- medi- General ates Structure Chemical Name SubstrateProcedure I-g-8

(2S,5′S)-N- (2,4-dichloro- benzyl)-5′- fluoro-6′,7′- dihydro- 5′H-spiro[oxirane-2,8′- quinoline]- 5′-carboxamide

G I-g-9

(2R,5′S)-N- (2,4-dichloro- benzyl)-5′- fluoro-6′,7′- dihydro- 5′H-spiro[oxirane-2,8′- quinoline]- 5′-carboxamide I-g-10

(2R,5′R)-N- (2,4-dichloro- benzyl)-5′- fluoro-6′,7′- dihydro- 5′H-spiro[oxirane-2,8′- quinoline]- 5′-carboxamide

H I-g-11

(2R,5′S)-N- (2,4-dichloro- benzyl)- 5′-fluoro-6′,7′- dihydro-5′H-spiro[oxirane- 2,8′-quinoline]- 5′-carboxamide I-g-12

(2S,5′S)-N- (2-chloro-4- fluorobenzyl)- 5′-fluoro-6′,7′- dihydro-5′H-spiro[oxirane-2,8′- quinoline]- 5′-carboxamide

G I-g-13

(2R,5′S)-N- (2-chloro-4- fluorobenzyl)- 5′-fluoro-6′,7′- dihydro-5′H-spiro[oxirane-2,8′- quinoline]- 5′-carboxamide I-g-14

(2S,5′S)-N- (2,4-dichloro-6- (hydroxymethyl) benzyl)-5′- fluoro-6′,7′-dihydro-5′H-spiro [oxirane-2,8′- quinoline]-5′- carboxamide

G I-g-15

(2R,5′S)-N- (2,4-dichloro-6- (hydroxymethyl) benzyl)-5′- fluoro-6′,7′-dihydro-5′H- spiro[oxirane- 2,8′-quinoline]-5′- carboxamide I-g-16

(2S,5′S)-N- (2-chloro-4- fluoro-6- (hydroxymethyl) benzyl)-5′-fluoro-6′,7′- dihydro-5′H- spiro[oxirane- 2,8′-quinoline]-5′-carboxamide

G I-g-17

(2S,5′S)-5′- fluoro-N-(2,3,4- trifluorobenzyl)- 6′,7′-dihydro- 5′H-spiro[oxirane-2,8′- quinoline]- 5′-carboxamide

G I-g-18

(2R,5′S)-5′- fluoro-N-(2,3,4- trifluorobenzyl)- 6′,7′-dihydro- 5′H-spiro[oxirane-2,8′- quinoline]-5′- carboxamide I-g-19

(2S,5′S)-N- (2,4- difluorobenzyl)- 5′-fluoro-6′7′- dihydro-5′H-spiro[oxirane- 2,8′-quinoline]-5′- carboxamide

G I-g-20

(2S,5′S)-N- (4-chloro-2- fluorobenzyl)- 5′-fluoro-6′,7′- dihydro-5′H-spiro[oxirane-2,8′- quinoline]-5′- carboxamide

G I-g-21

(2R,5′S)-N- (4-chloro-2- fluorobenzyl)- 5′-fluoro-6′,7′- dihydro-5′H-spiro[oxirane-2,8′- quinoline]- 5′-carboxamide I-g-22

(2S,5′S)-N- (2,4-dichloro-6- fluorobenzyl)- 5′-fluoro-6′,7′-dihydro-5′H- spiro[oxirane-2,8′- quinoline]- 5′-carboxamide

G I-g-23

(2S,5′S)-N- (2,4-dichloro-3- fluorobenzyl)- 5′-fluoro-6′,7′-dihydro-5′H- spiro[oxirane-2,8′- quinoline]-5′- carboxamide

G I-g-24

(2S,5′S)-N- (2,3-dichloro-4- fluorobenzyl)- 5′-fluoro-6′,7′-dihydro-5′H- spiro[oxirane-2,8′- quinoline]-5′- carboxamide

G I-g-25

(2S,5′S)-N-(2- chloro-4,6- difluorobenzyl)- 5′-fluoro-6′,7′-dihydro-5′H- spiro[oxirane-2,8′- quinoline]- 5′-carboxamide

G I-g-26

(2S,5′S)-N- (4-chloro-2,3- difluorobenzyl)- 5′-fluoro-6′,7′-dihydro-5′H- spiro[oxirane-2,8′- quinoline]-5′- carboxamide

G I-g-27

(2S,5′S)-N-(3- chloro-2,4- difluorobenzyl)- 5′-fluoro-6′,7′-dihydro-5′H- spiro[oxirane- 2,8′- quinoline]-5′- carboxamide

G I-g-28

(2S,5′S)-N- (4-chloro-2,6- difluorobenzyl)- 5′-fluoro-6′,7′-dihydro-5′H- spiro[oxirane- 2,8′- quinoline]-5′- carboxamide

G I-g-29

(2S,5′S)-N- ((R)-1-(2,4- dichlorophenyl) ethyl)-5′- fluoro-6′,7′-dihydro-5′H-spiro [oxirane-2,8′- quinoline]-5′- carboxamide

G I-g-30

(2S,5′S)-N- ((S)-1-(2,4- dichlorophenyl) ethyl)-5′-fluoro-6′,7′-dihydro- 5′H-spiro[oxirane- 2,8′-quinoline]- 5′-carboxamide

G I-g-31

(2S,5′S)-N- ((R)-1-(2-chloro- 4-fluorophenyl) ethyl)-5′- fluoro-6′,7′-dihydro-5′H-spiro [oxirane-2,8′- quinoline]-5′- carboxamide

G I-g-32

(2R,5′S)-N- ((R)-1-(2-chloro- 4-fluorophenyl) ethyl)-5′- fluoro-6′,7′-dihydro-5′H- spiro[oxirane- 2,8′-quinoline]-5′- carboxamide I-g-33

(2S,5′S)-N- ((S)-1-(2-chloro- 4-fluorophenyl) ethyl)-5′- fluoro-6′,7′-dihydro-5′H-spiro [oxirane-2,8′- quinoline]-5′- carboxamide

G I-g-34

(2S,5′S)-N- ((3,5-dichloro- pyridin-2-yl) methyl)-5′-fluoro-6′,7′-dihydro- 5′H-spiro[oxirane- 2,8′-quinoline]- 5′-carboxamide

G I-g-35

(2S,5′S)-N- (2,4-dichloro- phenethyl)-5′- fluoro-6′,7′- dihydro-5′H-spiro[oxirane-2,8′- quinoline]-5′- carboxamide

G I-g-36

(2S,5′S)-N-(2- (2,4-dichloro- phenyl) cyclopropyl)-5′- fluoro-6′,7′-dihydro-5′H- spiro[oxirane- 2,8′-quinoline]- 5′-carboxamide

G I-g-37

(5′S)-5′-fluoro- N-((1-morpholino- cyclohexyl) methyl)-6′,7′-dihydro-5′-spiro [oxirane-2,8′- quinoline]-5′- carboxamide

G I-g-38

(2S,5′S)-N- ((4-(2,4-dichloro phenyl)tetrahydro- 2H-pyran-4-yl)methyl)-5′- fluoro-6′,7′- dihydro-5′H- spiro[oxirane-2,8′-quinoline]-5′- carboxamide

G I-g-39

(2S,5′S)-N- (2,4-dichloro- benzyl)-5′-fluoro- 3′-methyl-6′,7′-dihydro-5′H-spiro [oxirane-2,8′- quinoline]-5′- carboxamide

G I-g-40

(2S,5′S)-N- (2-chloro-4- fluorobenzyl)- 5′-fluoro-3′- methyl-6′,7′-dihydro-5′H- spiro[oxirane- 2,8′-quinoline]-5′- carboxamide

G

IM II-g-8

¹H NMR and LCMS were identified with the IM I-g-4.

IM II-g-9

¹H NMR and LCMS were identified with the IM I-g-5.

IM II-g-10

¹H NMR and LCMS were identified with the IM I-g-4.

IM II-g-11

¹H NMR and LCMS were identified with the IM I-g-5.

IM I-g-12

¹H NMR and LCMS were identified with the IM I-g-6.

IM I-g-13

¹H NMR and LCMS were identified with the IM I-g-7.

IM I-g-14

¹H NMR (CDCl₃) delta 8.61 (1 H, br dd, J=4.9, 1.8 Hz), 7.59 (1 H, br),7.45 (1H, d, J=1.8 Hz), 7.43 (1 H, br dd, J=7.9, 1.8 Hz), 7.36 (1H, d,J=1.8 Hz), 7.21 (1H, dd, J=7.9, 4.9 Hz), 4.80 (1H, dd, J=14.7, 6.1 Hz),4.78 (2H, d, J=6.1 Hz), 4.71 (1H, dd, J=14.7, 6.1 Hz), 3.85 (1H, d,J=6.1 Hz), 3.73 (1H, t, J=6.1 Hz), 3.02 (1 H, d, J=6.1 Hz),2.71 (1H,m),2.54 (1H, m),2.29 (1H, m),2.10 (1H, m).

MS (ESI) m/z: 411.1 (M+H)⁺.

IM I-g-15

¹H NMR (DMSO-d6) delta 8.77 (1 H, br), 8.60 (1H, d, J=4.9 Hz), 7.64 (1H,d, J=7.9 Hz), 7.55 (1H, d, J=1.8 Hz), 7.48 (1H, d, J=1.8 Hz), 7.41 (1H,dd, J=7.9, 4.9 Hz), 5.52 (1H, t, J=5.5 Hz), 4.68 (2H, d, J=5.5 Hz), 4.51(1H, d, J=14.7 Hz), 4.46 (1H, d, J=14.7 Hz), 3.43 (1H, d, J=6.1 Hz),3.05 (1H, d, J=6.1 Hz), 2.50 (1H, m), 2.33-2.23 (2H, m), 2.13 (1H, m).

MS (ESI) m/z: 410.7 (M+H)⁺.

IM I-g-16

¹H NMR (CDCl₃) delta 8.61 (1H, ddd, J=4.9, 1.8, 1.2 Hz), 7.57 (1H, br d,J=6.1 Hz), 7.43 (1H, ddd, J=7.9, 1.8, 1.2 Hz), 7.20 (1H, dd, J=7.9, 4.9Hz), 7.18 (1H, dd, J=7.9, 2.4 Hz), 7.10 (1H, dd, J=8.6, 2.4 Hz),4.82-4.77 (3H, m), 4.71 (1H, dd, J=14.7, 6.1 Hz), 3.85 (1H, d, J=6.1Hz), 3.74 (1H, t, J=6.1 Hz), 3.02 (1H, d, J=6.1 Hz), 2.72 (1H, m), 2.54(1H, m), 2.29 (1H, m), 2.10 (1H, m).

MS (ESI) m/z: 394.8 (M+H)⁺.

IM I-g-17

¹H NMR (DMSO d6) delta 9.32 (1 H, br), 8.61 (1 H, br dd, J=4.9, 1.8 Hz),7.80 (1 H, br dd, J=7.9, 1.8 Hz), 7.61 (1H, dd, J=7.9, 4.9 Hz),7.35-7.16 (2H, m), 4.45 (2 H, m), 3.72 (1H, d, J=6.1 Hz), 3.03 (1H, d,J=6.1 Hz), 2.60-2.41 (2H, m), 2.27 (1 H, m), 1.90 (1H, m).

MS (ESI) m/z: 367.0 (M+H)⁺.

IM I-g-18

¹H NMR (DMSO-d6) delta 9.31 (1 H, br), 8.61 (1H, br d, J=4.9 Hz), 7.64(1 H, d, J=7.9 Hz), 7.41 (1H, dd, J=7.9, 4.9 Hz), 7.32 (1H, m), 7.22(1H, m), 4.45 (1 H, dd, J=15.3, 5.5 Hz), 4.41 (1H, dd, J=15.3, 5.5 Hz),3.43 (1H, d, J=6.1 Hz), 3.05 (1H, d, J=6.1 Hz), 2.50 (1H, m), 2.38-2.23(2H, m), 2.12 (1H, m).

MS (ESI) m/z: 367.0 (M+H)⁺.

IM I-g-19

¹H NMR (CDCl₃) delta 8.65 (1 H, br dd, J=4.9, 1.8 Hz), 7.52 (1 H, br dd,J=7.9, 1.8 Hz), 7.41 (1H, m), 7.25 (1 H, br dd, J=7.9, 4.9 Hz), 7.17(1H, br d, J=6.1 Hz), 6.96-6.87 (2H, m), 4.66 (1H, dd, J=14.7, 6.1 Hz),4.58 (1H, dd, J=14.7, 6.1 Hz), 3.89 (1H, d, J=6.1 Hz), 3.05 (1H, d,J=6.1 Hz), 2.79 (1H, m), 2.60 (1H, m), 2.34 (1H, m),2.15 (1H, m).

MS (ESI) m/z: 349.9 (M+H)⁺. IM I-g-20

¹H NMR (CDCl₃) delta 8.63 (1 H, br dd, J=4.9, 1.8 Hz), 7.49 (1 H, br dd,J=7.9, 1.8 Hz), 7.35 (1H, m), 7.23 (1 H, br dd, J=7.9, 4.9 Hz),7.19-7.11 (3H, m), 4.64 (1H, dd, J=14.7, 6.1 Hz), 4.56 (1H, dd, J=14.7,6.1 Hz), 3.87 (1H, d, J=6.1 Hz), 3.03 (1 H, d, J=6.1 Hz), 2.77 (1H, m),2.58 (1H, m), 2.32 (1H, m), 2.13 (1H, m).

MS (ESI) m/z: 364.8 (M+H)⁺.

IM I-g-21

¹H NMR (CDCl₃) delta 8.65 (1 H, br dd, J=4.9, 1.8 Hz), 7.53 (1 H, br dd,J=7.9, 1.8 Hz), 7.34 (1H, dd, J=7.9, 6.7 Hz), 7.25 (1H, dd, J=7.9, 4.9Hz), 7.26-7.13 (3H, m), 4.65 (1H, dd, J=14.7, 6.1 Hz), 4.57 (1H, dd,J=14.7, 6.1 Hz), 3.52 (1H, d, J=6.1 Hz), 3.08 (1H, d, J=6.1 Hz), 2.67(1H, m), 2.53-2.40 (2H, m), 2.19 (1H, m).

MS (ESI) m/z: 364.8 (M+H)⁺.

IM I-g-22

¹H NMR (CDCl₃) delta 8.62 (1 H, br dd, J=4.9, 1.8 Hz), 7.53 (1 H, br dd,J=7.9, 1.8 Hz),7.31 (1H, d, J=1.8 Hz), 7.24 (1H, br dd, J=7.9, 4.9Hz),7.12 (1H, dd, J=8.6, 1.8 Hz), 7.02 (1 H, br), 4.78 (1H, dd, J=14.7,6.1 Hz), 4.69 (1H, dd, J=14.7, 6.1 Hz), 3.85 (1H, d, J=6.1 Hz), 3.02(1H, d, J=6.1 Hz), 2.76 (1H, m), 2.56 (1H, m), 2.31 (1H, m), 2.14 (1H,m).

MS (ESI) m/z: 398.7 (M+H)⁺.

IM I-g-23

¹H NMR (CDCl₃) delta 8.63 (1 H, br dd, J=4.9, 1.8 Hz), 7.50 (1 H, br dd,J=7.9, 1.8 Hz), 7.34 (1 H, br dd, J=7.9, 4.9 Hz), 7.26-7.18 (3H, m),4.69 (1H, dd, J=14.7, 6.1 Hz), 4.65 (1H, dd, J=14.7, 6.1 Hz), 3.86 (1H,d, J=6.1 Hz), 3.03 (1H, d, J=6.1 Hz), 2.76 (1H, m), 2.57 (1H, m), 2.33(1H, m), 2.14 (1H, m).

MS (ESI) m/z: 398.8 (M+H)⁺.

IM I-g-24

¹H NMR (CDCl₃) delta 8.63 (1 H, br dd, J=4.9, 1.8 Hz), 7.49 (1 H, br dd,J=7.9, 1.8 Hz), 7.38 (1H, dd, J=8.6, 5.5 Hz), 7.24 (1 H, br dd, J=7.9,4.9 Hz), 7.25-7.22 (1 H, br), 7.12 (1H, dd, J=8.6, 7.9 Hz), 4.69 (1H,dd, J=15.3, 6.1 Hz), 4.65 (1 H, dd, J=15.3, 6.1 Hz), 3.86 (1H, d, J=6.1Hz), 3.03 (1H, d, J=6.1 Hz), 2.76 (1H, m), 2.57 (1H, m),2.32 (1H,m),2.14 (1H, m).

MS (ESI) m/z: 398.8 (M+H)⁺.

IM I-g-25

¹H NMR (CDCl₃) delta 8.62 (1 H, br dd, J=4.9, 1.8 Hz), 7.54 (1 H, br dd,J=7.9, 1.8 Hz), 7.24 (1H, m), 7.06 (1 H, br dd, J=7.9, 4.9 Hz), 7.01 (1H, br), 6.86 (1H, m), 4.78 (1H, dd, J=14.7, 5.5 Hz), 4.68 (1H, dd,J=14.7, 5.5 Hz), 3.86 (1H, d, J=6.1 Hz), 3.02 (1H, d, J=6.1 Hz), 2.76(1H, m), 2.56 (1H, m), 2.32 (1H, m), 2.14 (1H, m).

MS (ESI) m/z: 382.8 (M+H)⁺.

IM I-g-26

¹H NMR (CDCl₃) delta 8.63 (1 H, br dd, J=4.9, 1.8 Hz), 7.50 (1 H, br dd,J=7.9, 1.8 Hz), 7.28-7.08 (4H, m), 4.66 (1H, dd, J=14.7, 6.7 Hz), 4.61(1H, dd, J=14.7, 6.7 Hz), 3.87 (1H, br d, J=6.1 Hz), 3.03 (1H, br d,J=6.1 Hz), 2.76 (1H, m), 2.57 (1 H, m), 2.33 (1H, m), 2.15 (1H, m).

MS (ESI) m/z: 382.8 (M+H)⁺.

IM I-g-27

¹H NMR (CDCl₃) delta 8.63 (1 H, br dd, J=4.9, 1.8 Hz), 7.49 (1 H, br dd,J=7.9, 1.8 Hz), 7.31 (1H, m), 7.24 (1 H, br dd, J=7.9, 4.9 Hz), 7.19 (1H, br), 7.00 (1H, ddd, J=8.6, 4.3, 1.8 Hz),4.64 (1H, dd, J=14.7, 6.1Hz), 4.59 (1H, dd, J=14.7, 6.1 Hz), 3.87 (1H, d, J=6.1 Hz), 3.03 (1H, d,J=6.1 Hz), 2.76 (1H, m), 2.57 (1H, m), 2.32 (1H, m), 2.13 (1H, m).

MS (ESI) m/z: 382.8 (M+H)⁺.

IM I-g-28

¹H NMR (CDCl₃) delta 8.62 (1 H, br dd, J=4.3, 1.8 Hz), 7.51 (1 H, br dd,J=7.9, 1.8 Hz), 7.24 (1 H, br dd, J=7.9, 4.3 Hz), 7.06-6.99 (3H, m),4.71 (1H, dd, J=14.7, 5.5 Hz), 4.61 (1H, dd, J=14.7, 4.9 Hz), 3.86 (1H,d, J=6.1 Hz), 3.02 (1H, d, J=6.1 Hz), 2.74 (1H, m), 2.56 (1H, m), 2.30(1H, m), 2.13 (1H, m).

MS (ESI) m/z: 382.8 (M+H)⁺.

IM I-g-29

¹H NMR (CDCl₃) delta 8.60 (1 H, br dd, J=4.9, 1.8 Hz), 7.45 (1H, d,J=1.8 Hz), 7.44 (1 H, br dd, J=7.9, 1.8 Hz), 7.37 (1H, d, J=8.6 Hz),7.30 (1H, dd, J=8.6, 1.8 Hz), 7.19 (1H, dd, J=7.9, 4.9 Hz), 7.13 (1 H,br), 5.47 (1H, m), 3.85 (1H, d, J=6.1 Hz), 3.02 (1H, d, J=6.1 Hz), 2.78(1H, m), 2.58 (1H, m), 2.35 (1H, m), 2.16 (1H, m), 1.60 (3H, d, J=7.3Hz).

MS (ESI) m/z: 395.3 (M+H)⁺.

IM I-g-30

¹H NMR (CDCl₃) delta 8.64 (1 H, br dd, J=4.9, 1.8 Hz), 7.61 (1 H, br dd,J=7.9, 1.8 Hz), 7.42 (1H, d, J=1.8 Hz), 7.31-7.26 (3H, m), 7.17 (1H, dd,J=6.7, 6.1 Hz), 5.45 (1H, m), 3.86 (1H, d, J=6.1 Hz), 3.01 (1H, d, J=6.1Hz), 2.77-2.51 (2H, m), 2.27 (1H, m), 2.10 (1H, m), 1.62 (3H, d, J=7.3Hz).

MS (ESI) m/z: 395.2 (M+H)⁺.

IM I-g-31

¹H NMR (CDCl₃) delta 8.59 (1 H, br dd, J=4.3, 1.8 Hz), 7.45 (1 H, br dd,J=7.9, 1.8 Hz), 7.41 (1H, dd, J=8.6, 6.1 Hz), 7.18 (1H, dd, J=7.9, 4.3Hz), 7.16 (1 H, dd, J=6.1, 3.1 Hz), 7.14 (1 H, br), 7.03 (1H, ddd,J=8.5, 7.9, 3.1 Hz), 5.46 (1H, m), 3.85 (1H, d, J=6.1 Hz), 3.02 (1H, d,J=6.1 Hz), 2.77 (1H, m),2.57 (1H, m),2.34 (1H, m), 2.15 (1H, m), 1.60(3H, d, J=6.7 Hz).

MS (ESI) m/z: 379.2 (M+H)⁺.

IM I-g-32

¹H NMR (CDCl₃) delta 8.59 (1 H, br dd, J=4.9, 1.8 Hz), 7.45 (1H, ddd,J=7.9, 1.8, 1.2 Hz), 7.40 (1H, dd, J=8.6, 6.1 Hz), 7.18 (1H, dd, J=8.6,2.4 Hz), 7.16 (1 H, dd, J=7.9, 4.9 Hz), 7.14 (1 H, br), 7.04 (1H, ddd,J=8.6, 7.9, 2.4 Hz), 5.45 (1H, m), 3.50 (1H, d, J=6.1 Hz), 3.05 (1H, d,J=6.1 Hz), 2.67 (1H, m), 2.50-2.42 (2H, m), 2.22 (1H, m), 1.60 (3H, d,J=6.7 Hz).

MS (ESI) m/z: 379.2 (M+H)⁺.

IM I-g-33

¹H NMR (CDCl₃) delta 8.64 (1H, ddd, J=4.9, 1.8, 1.2 Hz), 7.61 (1H, ddd,J=7.9, 1.8, 1.2 Hz), 7.36 (1H, dd, J=8.6, 6.1 Hz), 7.28 (1H, dd, J=7.9,4.9 Hz), 7.16 (1H, dd, J=8.6, 3.1 Hz), 7.13 (1 H, br), 7.02 (1 H, dt,J=8.6, 3.1 Hz), 5.46 (1H, m), 3.86 (1H, d, J=6.1 Hz), 3.02 (1H, d, J=6.1Hz), 2.78-2.52 (2H, m),2.28 (1H, m),2.10 (1H, m), 1.63 (3H, d, J=6.7Hz).

MS (ESI) m/z: 378.9 (M+H)⁺.

IM I-g-34

¹H NMR (CDCl₃) delta 8.64 (1 H, br dd, J=4.3, 1.8 Hz), 8.47 (1H, d,J=2.4 Hz), 8.10 (1 H, br), 7.78 (1H, d, J=2.4 Hz), 7.74 (1H, dd, J=7.9,1.8 Hz), 7.26 (1 H, dd, J=7.9, 4.3 Hz), 4.83 (1H, dd, J=18.3, 4.9 Hz),4.71 (1H, dd, J=18.3, 4.9 Hz), 3.89 (1 H, d, J=6.1 Hz), 3.05 (1H, d,J=6.1 Hz), 2.83 (1H, m), 2.62 (1H, m), 2.40 (1H, m), 2.16 (1H, m).

MS (ESI) m/z: 382.5 (M+H)⁺.

IM I-g-35

¹H NMR (CDCl₃) delta 8.61 (1H, br d, J=4.3 Hz), 7.43 (1 H, s), 7.33 (1H,d, J=7.9 Hz), 7.25-7.19 (2H, m), 7.21 (1H, dd, J=7.9, 4.3 Hz), 6.86 (1H,br d, J=4.9 Hz), 3.86 (1H, d, J=6.1 Hz), 3.79-3.63 (2H, m), 3.08-3.04(2H, m), 3.02 (1H, d, J=6.1 Hz), 2.72 (1H, m), 2.55 (1H, m), 2.26 (1H,m), 2.12 (1H, m).

MS (ESI) m/z: 395.0 (M+H)⁺.

IM I-g-36

¹H NMR (CDCl₃) delta 8.65 (1H, m), 7.59 (1H, m), 7.40 (1H, d, J=1.8 Hz),7.27 (1H, m),7.19 (1H, m),7.12 (1H, d, J=8.6 Hz), 7.03 (1H, br), 3.88(0.5H, d, J=6.1 Hz), 3.87 (0.5 H, d, J=6.1 Hz), 3.10 (1H, m), 3.03 (1H,d, J=6.1 Hz), 2.79 (1H, m), 2.60 (1H, m), 2.39-2.29 (2H, m), 2.15 (1H,m), 1.43-1.31 (2H, m).

MS (ESI) m/z: 407.3 (M+H)⁺.

IM I-g-37

¹H NMR (CDCl₃) delta 8.63 (1H, ddd, J=4.3, 1.8, 1.8 Hz), 7.55 (1H, dd,J=7.9, 1.8 Hz), 7.39 (1 H, br), 7.25 (1H, m), 3.87 (0.7 H, d, J=6.1 Hz),3.7.-3.69 (4H, m), 3.54-3.42 (2.3 H, m), 3.06 (0.3 H, d, J=6.1 Hz), 3.03(0.7 H, d, J=6.1 Hz), 2.85-2.38 (6H, m), 2.31 (1H, m), 2.15 (1H, m),1.76-1.46 (10H, m).

MS (ESI) m/z: 404.2 (M+H)⁺.

IM I-g-38

¹H NMR (CDCl₃) delta 8.60 (1H, br d, J=4.9 Hz), 7.47 (1H, d, J=1.8 Hz),7.34-7.29 (2H, m), 7.18 (1H, dd, J=7.9, 4.9 Hz), 7.10 (1H, br d, J=7.9Hz),6.40 (1 H, br d, J=6.7 Hz),4.21 (1H, dd, J=14.1, 6.7 Hz), 3.99 (1H,dd, J=14.1, 6.1 Hz), 3.93-3.84 (2H, m), 3.81 (1H, d, J=6.1 Hz),3.74-3.62 (2H, m), 2.99 (1H, d, J=6.1 Hz), 2.60 (1H, m), 2.50-2.34 (3H,m), 2.19-2.04 (4H, m).

MS (ESI) m/z: 465.0 (M+H)⁺.

IM I-g-39

¹H NMR (CDCl₃) delta 8.44 (1 H, br), 7.46 (1H, d, J=1.8 Hz), 7.39 (1H,m), 7.29-7.22 (3H, m), 4.71-4.59 (2H, m), 3.85 (1H, d, J=6.1 Hz), 3.00(1H, d, J=6.1 Hz), 2.76 (1H, m), 2.57 (1H, m), 2.29 (1H, m), 2.27 (3 H,s), 2.09 (1H, m).

MS (ESI) m/z: 395.0 (M+H)⁺.

IM I-g-40

¹H NMR (CDCl₃) delta 8.44 (1 H, br), 7.46 (1H, dd, J=8.6, 6.1 Hz),7.20-7.14 (3H, m), 7.02 (1H, ddd, J=8.6, 7.9, 3.1 Hz), 4.69 (1H, dd,J=14.7, 6.1 Hz), 4.62 (1H, dd, J=14.7, 6.1 Hz), 3.86 (1H, d, J=6.1 Hz),3.01 (1H, d, J=6.1 Hz), 2.76 (1H, m), 2.58 (1H, m), 2.29 (1H, m), 2.27(3 H, s), 2.07 (1H, m).

MS (ESI) m/z: 379.4 (M+H)⁺.

The following Examples and Intermediates were prepared by GeneralProcedure J, K, P, Q, R, or S (Tables 46 and 48).

General Procedure P

A mixture of substrate (1.0 eq.), LiClO₄ (1.5 eq.), and KCN (1.5 eq.) inMeCN was heated at reflux. After being stirred at reflux until completereaction, the mixture was cooled to room temperature. Water was added tothe mixture, and the mixture was extracted with EtOAc twice. Theextracts were washed with brine, dried over Na₂SO₄, and concentrated invacuo. The residue was purified by silica gel column chromatography andpreparative HPLC to afford following Examples.

General Procedure Q

The substrate (1.0 eq.) was dissolved with 1.0 M TBAF in THF (12.0 eq.)and the mixture was heated at 70° C. until complete reaction. Themixture was cooled to room temperature and water was added to themixture. The mixture was extracted with EtOAc and washed with brine. Theextract was dried over Na₂SO₄ and concentrated in vacuo. The resultingmixture was purified by silica gel column chromatography and preparativeHPLC to afford the following Examples.

General Procedure R

Fifteen percent of sodium thiomethoxide in water (3.0 eq.) was added tothe solution of substrate (1.0 eq.) in THF. The mixture was stirred at60° C. until complete reaction and then cooled to room temperature.Water was added to the mixture and extracted with EtOAc twice. Theextracts were dried over Na₂SO₄ and concentrated in vacuo. The resultingresidue was purified by silica gel column chromatography and preparativeHPLC to afford the following Examples and Intermediates.

General Procedure S

To a mixture of substrate (1.0 eq.) and K₂CO₃ (2.0 eq.) in acetone wasadded mercaptoethanol (4.4 eq.) at ambient temperature. The mixture wasstirred at 70° C. until complete reaction and cooled to roomtemperature. The volatile was removed under reduced pressure and waterwas added to the mixture. The mixture was extracted with EtOAc, driedover Na₂SO₄, and concentrated in vacuo. The resulting residue waspurified by silica gel column chromatography and preparative HPLC toafford the following Examples and Intermediates.

TABLE 46 Ex- General am- Procedure ples Structure Chemical NameSubstrate (/Amine) 256

(5S,8S)-N-(2,4- dichlorobenzyl)-5- fluoro-8-hydroxy- 8-methyl-5,6,7,8-tetrahydroquinoline- 5-carboxamide

K 257

(5S,8R)-N-(2,4- dichlorobenzyl)-5- fluoro-8-hydroxy- 8-methyl-5,6,7,8-tetrahydroquinoline- 5-carboxamide

K 258

(5S,8S)-5-fluoro-8- hydroxy-8- methyl-N-(2,3,4- trifluorobenzyl)-5,6,7,8- tetrahydroquinoline- 5-carboxamide

K 259

(5S,8S)-N- (2-chloro-4- fluorobenzyl)- 5-fluoro-8- hydroxy-8-methyl-5,6,7,8- tetrahydroquinoline- 5-carboxamide

K 260

(5S,8R)-N- (2-chloro-4- fluorobenzyl)- 5-fluoro-8- hydroxy-8-methyl-5,6,7,8- tetrahydroquinoline- 5-carboxamide

K 261

(5S,8S)-N- (2,4-dichloro- 6-(hydroxymethyl) benzyl)-5-fluoro-8-hydroxy-8- methyl-5,6,7,8- tetrahydroquinoline- 5-carboxamide

K 262

(5S,8S)-N- (2-chloro-4- fluoro-6- (hydroxymethyl) benzyl)-5-fluoro-8-hydroxy-8-methyl- 5,6,7,8- tetrahydroquinoline- 5-carboxamide

K 263

(5S,8S)-N-(2,4- difluorobenzyl)-5- fluoro-8-hydroxy- 8-methyl-5,6,7,8-tetrahydroquinoline- 5-carboxamide

K 264

(5S,8S)-N- (4-chloro-2- fluorobenzyl)- 5-fluoro-8- hydroxy-8-methyl-5,6,7,8- tetrahydroquinoline- 5-carboxamide

K 265

(5S,8S)-N- (2,4-dichloro- 6-fluorobenzyl)- 5-fluoro- 8-hydroxy-8-methyl-5,6,7,8- tetrahydroquinoline- 5-carboxamide

K 266

(5S,8S)-N- (2-chloro-4,6- difluorobenzyl)- 5-fluoro- 8-hydroxy-8-methyl-5,6,7,8- tetrahydroquinoline- 5-carboxamide

K 267

(5S,8S)-N- (4-chloro-2,3- difluorobenzyl)- 5-fluoro- 8-hydroxy-8-methyl-5,6,7,8- tetrahydroquinoline- 5-carboxamide

K 268

(5S,8S)-N- (3-chloro-2,4- difluorobenzyl)- 5-fluoro-8- hydroxy-8-methyl-5,6,7,8- tetrahydroquinoline- 5-carboxamide

K 269

(5S,8S)-N- (4-chloro-2,6- difluorobenzyl)- 5-fluoro-8- hydroxy-8-methyl-5,6,7,8- tetrahydroquinoline- 5-carboxamide

K 270

(5S,8S)-N-((R)- 1-(2-chloro-4- fluorophenyl) ethyl)-5-fluoro-8-hydroxy-8-methyl- 5,6,7,8- tetrahydroquinoline- 5-carboxamide

K 271

(5S,8S)-N-((S)- 1-(2-chloro-4- fluorophenyl) ethyl)-5-fluoro-8-hydroxy-8- methyl-5,6,7,8- tetrahydroquinoline- 5-carboxamide

K 272

(5S,8S)-N-((3,5- dichloropyridin-2- yl)methyl)-5-fluoro- 8-hydroxy-8-methyl-5,6,7,8- tetrahydroquinoline- 5-carboxamide

K 273

(5S,8S)-N- ((trans)-2-(2,4- dichlorophenyl) cyclopropyl)- 5-fluoro-8-hydroxy-8- methyl-5,6,7,8- tetrahydroquinoline- 5-carboxamide

K 274

(5S,8S)-5-fluoro-8- hydroxy-8- methyl-N-((1- morpholinocyclohexyl)methyl)-5,6,7,8- tetrahydroquinoline- 5-carboxamide

K 275

(5S,8R)-5-fluoro-8- hydroxy-8- methyl-N-((1- morpholinocyclohexyl)methyl)-5,6,7,8- tetrahydroquinoline- 5-carboxamide 276

(5S,8S)-N- (2-chloro-4- fluorobenzyl)- 5-fluoro-8- hydroxy-3,8-dimethyl-5,6,7,8- tetrahydroquinoline- 5-carboxamide

K 277

(5S,8R)-N-(2,4- dichlorobenzyl)-5- fluoro-8-hydroxy-8-(((2-hydroxyethyl) (methyl)amino) methyl)-5,6,7,8-tetrahydroquinoline- 5-carboxamide

J/

278

(5R,8S)-N-(2,4- dichlorobenzyl)-5- fluoro-8-hydroxy-8-(((2-hydroxyethyl) (methyl)amino) methyl)-5,6,7,8-tetrahydroquinoline- 5-carboxamide

J/

279

(5R,8S)-N-(2,4- dichlorobenzyl)-5- fluoro-8-hydroxy-8-((3-hydroxyazetidin- 1-yl)methyl)-5,6,7,8- tetrahydroquinoline-5-carboxamide

J/

280

(5S,8R)-8- (cyanomethyl)- N-(2,4- dichlorobenzyl)- 5-fluoro-8-hydroxy-5,6,7,8- tetrahydroquinoline- 5-carboxamide

P 281

(5S,8R)-N- (2-chloro-4- fluorobenzyl)-8- (cyanomethyl)-5-fluoro-8-hydroxy- 5,6,7,8- tetrahydroquinoline- 5-carboxamide

P 282

(5S,8S)-N- (2-chloro-4- fluorobenzyl)-8- (cyanomethyl)-5-fluoro-8-hydroxy- 5,6,7,8- tetrahydroquinoline- 5-carboxamide

P 283

(5S,8R)-8- (cyanomethyl)- N-(2,4-dichloro-6- hydroxymethyl)benzyl)-5-fluoro-8- hydroxy-5,6,7,8- tetrahydroquinoline- 5-carboxamide

P 284

(5S,8R)-N- (2-chloro-4- fluoro-6- (hydroxymethyl) benzyl)-8-(cyanomethyl)- 5-fluoro-8-hydroxy- 5,6,7,8- tetrahydroquinoline-5-carboxamide

P 285

(5S,8S)-N-(2,4- dichlorobenzyl)-5- fluoro-8- (fluoromethyl)-8-hydroxy-5,6,7,8- tetrahydroquinoline- 5-carboxamide

Q 286

(5S,8S)-N- (2-chloro-4- fluorobenzyl)- 5-fluoro-8- (fluoromethyl)-8-hydroxy-5,6,7,8- tetrahydroquinoline- 5-carboxamide

Q 287

(5S,8S)-N-(2,4- dichlorobenzyl)-5- fluoro-8-hydroxy-8((methylthio)methyl)- 5,6,7,8- tetrahydroquinoline- 5-carboxamide

R 288

(5S,8S)-N- (2-chloro-4- fluorobenzyl)- 5-fluoro-8- hydroxy-8-((methylthio) methyl)-5,6,7,8- tetrahydroquinoline- 5-carboxamide

R 289

(5S,8S)-N- (2-chloro-4- fluorobenzyl)- 5-fluoro-8- hydroxy-8-(((2-hydroxyethyl)thio) methyl)-5,6,7,8- tetrahydroquinoline- 5-carboxamide

S

TABLE 47 LC MS Examples Method tR (min) [M + H]⁺ 256 C 1.57 382.9 257 C1.57 383.0 258 C 1.43 369.0 259 C 1.47 367.0 260 C 1.45 366.9 261 C 1.43412.9 262 D 1.37 397.1 263 C 1.37 351.1 264 C 1.48 367.1 265 C 1.57401.0 266 D 1.54 385.0 267 D 1.59 385.0 268 D 1.58 385.0 269 D 1.57385.0 270 D 1.61 381.1 271 D 1.62 381.1 272 D 1.54 384.0 273 D 1.79409.1 274 D 1.61 406.2 275 D 1.58 406.2 276 D 1.63 381.1 280 D 1.66408.0 281 D 1.55 392.1 282 D 1.54 392.1 283 D 1.49 438.1 284 D 1.37422.0 285 D 1.70 401.0 286 D 1.58 385.1 287 D 1.78 429.0 288 D 1.67413.1 289 D 1.44 443.1¹H NMR (CDCl₃) delta 8.60 (1H, ddd, J=4.9, 1.8, 1.2 Hz), 7.49 (1H, ddd,J=7.9, 1.8, 1.2 Hz),7.44 (1H, d, J=2.4 Hz), 7.36 (1H, d, J=7.9 Hz), 7.23(1H, dd, J=7.9, 2.4 Hz), 7.21 (1H, dd, J=7.9, 4.9 Hz), 7.13 (1 H, br d,J=5.5.Hz), 4.62 (1H, dd, J=14.7, 6.1 Hz), 4.57 (1H, dd, J=14.7, 6.1 Hz),3.26 (1 H, br s), 2.65 (1H, m), 2.38 (1 H, m), 2.22-2.11 (2H, m), 1.63(3 H, s).

Ex 257

¹H NMR (CDCl₃) delta 8.60 (1 H, br dd, J=4.9, 1.8 Hz), 7.46 (1H, d,J=1.8 Hz), 7.45 (1H, ddd, J=7.9, 1.8, 1.2 Hz), 7.39-7.20 (4H, m), 4.66(1H, dd, J=14.7, 6.1 Hz), 4.59 (1H, dd, J=14.7, 6.1 Hz), 4.00 (1 H, brs), 2.60 (1H, m), 2.36-2.23 (2H, m), 2.16 (1H, m), 1.56 (3 H, s).

Ex 258

¹H NMR (CDCl₃) delta 8.61 (1H, ddd, J=4.9, 1.8, 1.2 Hz), 7.49 (1H, ddd,J=7.9, 1.8, 1.2 Hz), 7.22 (1H, dd, J=7.9, 4.9 Hz), 7.14-7.08 (2H, m),6.97 (1H, m), 4.61 (1 H, dd, J=14.7, 6.1 Hz), 4.55 (1H, dd, J=14.7, 6.1Hz), 3.30 (1 H, br s), 2.65 (1H, m), 2.37 (1H, m), 2.22-2.11 (2H, m),1.63 (3 H, s).

Ex 259

¹H NMR (CDCl₃) delta 8.61 (1H, ddd, J=4.9, 1.8, 1.2 Hz), 7.50 (1H, ddd,J=7.9, 1.8, 1.2 Hz), 7.41 (1H, dd, J=8.6, 5.5 Hz), 7.22 (1H, dd, J=7.9,4.9 Hz), 7.18 (1H, dd, J=8.6, 2.4 Hz), 7.11 (1H, br d, J=5.5 Hz), 6.99(1 H, ddd, J=8.6, 7.9, 2.4.Hz), 4.63 (1H, dd, J=14.7, 6.1 Hz), 4.57 (1H,dd, J=14.7, 6.1 Hz), 3.18 (1 H, br s), 2.65 (1H, m), 2.39 (1H, m),2.23-2.10 (2H, m), 1.63 (3 H, s).

Ex 260

¹H NMR (CDCl₃) delta 8.60 (1 H, br dd, J=4.9, 1.8 Hz), 7.45-7.41 (2H,m), 7.26-7.18 (3H, m), 7.00 (1H, ddd, J=8.6, 7.9, 2.4 Hz), 4.66 (1H, dd,J=14.7, 6.1 Hz), 4.59 (1H, dd, J=14.7, 5.5 Hz), 4.03 (1 H, s), 2.59 (1H,m), 2.36-2.23 (2H, m), 2.14 (1H, m), 1.56 (3 H, s).

Ex 261

¹H NMR (CDCl₃) delta 8.57 (1H, ddd, J=4.9, 1.8, 1.2 Hz), 7.52 (1H, br d,J=5.5 Hz), 7.43-7.41 (2H, m), 7.33 (1H, d, J=1.8 Hz), 7.18 (1H, dd,J=7.9, 4.9 Hz), 4.76-4.69 (3H, m), 4.64 (1H, dd, J=14.7, 6.1 Hz), 3.99(1 H, br), 3.43 (1 H, br), 2.60 (1H, m), 2.32 (1H, m), 2.17-2.04 (2H,m), 1.61 (3 H, s).

Ex 262

¹H NMR (CDCl₃) delta 8.60 (1H, ddd, J=4.9, 1.8, 1.2 Hz), 7.51 (1H, br d,J=5.5 Hz),7.43 (1H, br d, J=7.9 Hz),7.19 (1H, dd, J=7.9, 4.9 Hz), 7.17(1H, dd, J=7.9, 2.4 Hz), 7.09 (1H, dd, J=8.6, 2.4 Hz), 4.79-4.62 (3H,m), 4.66 (1H, dd, J=14.7, 6.1 Hz), 3.79 (1 H, br), 3.21 (1 H, br), 2.60(1H, m), 2.33 (1H, m), 2.19-2.08 (2H, m), 1.63 (3 H, s).

Ex 263

¹H NMR (CDCl₃) delta 8.60 (1H, ddd, J=4.9, 1.8, 1.2 Hz), 7.49 (1H, d,J=7.9 Hz), 7.36 (1H, dd, J=8.6, 6.1 Hz), 7.21 (1H, dd, J=7.9, 4.9 Hz),7.07 (1H, br d, J=4.9 Hz), 6.90-6.84 (2H, m), 4.59 (1H, dd, J=14.7, 6.1Hz), 4.52 (1H, dd, J=14.7, 6.1 Hz), 3.28 (1 H, br), 2.66 (1H, m), 2.38(1H, m), 2.22-2.11 (2H, m), 1.63 (3 H, s).

Ex 264

¹H NMR (CDCl₃) delta 8.60 (1H, ddd, J=4.9, 1.8, 1.2 Hz), 7.49 (1H, ddd,J=7.9, 1.8, 1.2 Hz), 7.31 (1H, t, J=7.9 Hz), 7.21 (1H, dd, J=7.9, 4.9Hz), 7.16-7.08 (3H, m), 4.59 (1H, dd, J=14.7, 6.1 Hz), 4.52 (1H, dd,J=14.7, 6.1 Hz), 3.31 (1 H, br s), 2.66 (1H, m), 2.38 (1H, m), 2.22-2.11(2H, m), 1.63 (3 H, s).

Ex 265

¹H NMR (CDCl₃) delta 8.60 (1H, ddd, J=4.9, 1.8, 1.2 Hz), 7.51 (1H, ddd,J=7.9, 1.8, 1.2 Hz), 7.29 (1H, dd, J=1.8, 1.2 Hz), 7.21 (1H, dd, J=7.9,4.9 Hz), 7.10 (1H, dd, J=9.2, 1.8 Hz), 6.97 (1H, br d, J=5.5 Hz), 4.74(1H, dd, J=14.7, 6.1 Hz), 4.64 (1H, dd, J=14.7, 5.5 Hz), 3.29 (1H, brs), 2.66 (1H, m), 2.38 (1H, m), 2.21-2.10 (2 H, m), 1.63 (3 H, s).

Ex 266

¹H NMR (CDCl₃) delta 8.59 (1H, ddd, J=4.9, 1.8, 1.2 Hz), 7.52 (1H, ddd,J=7.9, 1.8, 1.2 Hz), 7.21 (1H, dd, J=7.9, 4.9 Hz), 7.04 (1 H, br dd,J=7.9, 2.4 Hz), 6.96 (1 H, br d, J=5.5 Hz), 6.84 (1 H, br dt, J=8.6, 2.4Hz), 4.74 (1H, dd, J=14.7, 6.1 Hz), 4.64 (1H, dd, J=14.7, 5.5 Hz), 3.32(1 H, br s), 2.67 (1H, m), 2.32 (1H, m), 2.21-2.10 (2H, m), 1.63 (3 H,s).

Ex 267

¹H NMR (CDCl₃) delta 8.61 (1H, m), 7.49 (1H, dd, J=7.9, 1.2 Hz),7.25-7.08 (4H, m), 4.62 (1H, dd, J=15.3, 6.1 Hz), 4.56 (1H, dd, J=15.3,6.7 Hz), 3.30 (1 H, br), 2.64 (1H, m), 2.38 (1H, m), 2.22-2.11 (2H, m),1.63 (3 H, s).

Ex 268

¹H NMR (CDCl₃) delta 8.61 (1H, ddd, J=4.9, 1.8, 1.2 Hz), 7.49 (1H, ddd,J=7.9, 1.8, 1.2 Hz), 7.28 (1H, m), 7.22 (1H, dd, J=7.9, 4.9 Hz), 7.11 (1H, br), 6.98 (1 H, dt, J=8.6, 1.8 Hz), 4.60 (1H, dd, J=14.7, 6.1 Hz),4.55 (1H, dd, J=14.7, 6.1 Hz), 3.29 (1 H, br s), 2.65 (1H, m), 2.38 (1H,m), 2.25-2.11 (2H, m), 1.63 (3 H, s).

Ex 269

¹H NMR (CDCl₃) delta 8.60 (1H, ddd, J=4.9, 1.8, 1.2 Hz), 7.50 (1H, d,J=7.9 Hz), 7.22 (1H, dd, J=7.9, 4.9 Hz), 7.04-6.95 (3H, m), 4.66 (1H,dd, J=14.7, 6.1 Hz), 4.57 (1H, dd, J=14.7, 5.5 Hz), 3.30 (1 H, br s),2.65 (1H, m), 2.37 (1H, m), 2.20-2.09 (2H, m), 1.63 (3 H, s).

Ex 270

¹H NMR (CDCl₃) delta 8.57 (1H, br d, J=4.9 Hz), 7.45 (1H, ddd, J=7.9,1.8, 1.2 Hz), 7.39 (1H, dd, J=8.6, 6.1 Hz), 7.17-7.14 (2H, m), 7.06 (1H,dd, J=6.7, 5.5 Hz), 7.02 (1H, ddd, J=8.6, 7.9, 2.4 Hz), 5.42 (1 H, dq,J=6.7, 6.7 Hz), 3.33 (1 H, br s), 2.68 (1H, m), 2.39 (1H, m), 2.24-2.13(2H, m), 1.63 (3 H, s), 1.59 (3H, d, J=6.7 Hz).

Ex 271

¹H NMR (CDCl₃) delta 8.62 (1H, ddd, J=4.9, 1.8, 1.2 Hz), 7.60 (1H, ddd,J=7.9, 1.8, 1.2 Hz), 7.34 (1H, dd, J=8.6, 5.5 Hz), 7.26 (1H, dd, J=7.9,4.9 Hz), 7.15 (1H, dd, J=8.6, 2.4 Hz), 7.07 (1H, dd, J=6.7, 5.5 Hz),7.01 (1H, ddd, J=8.6, 7.9, 2.4 Hz), 5.41 (1 H, dq, J=7.3, 6.7 Hz), 3.28(1 H, br s), 2.59 (1H, m), 2.33 (1H, m), 2.19-2.08 (2H, m), 1.63 (3 H,s), 1.59 (3H, d, J=7.3 Hz).

Ex 272

¹H NMR (CDCl₃) delta 8.63 (1H, br d, J=4.9 Hz), 8.48 (1H, d, J=2.4 Hz),8.03 (1 H, br d, J=4.3 Hz), 7.77 (1H, d, J=2.4 Hz), 7.72 (1H, d, J=7.9Hz), 7.24 (1 H, dd, J=7.9, 4.9 Hz), 4.78 (1H, dd, J=18.3, 4.9 Hz), 4.67(1H, dd, J=18.3, 4.3 Hz), 3.27 (1 H, br s), 2.72 (1H, m), 2.40 (1H, m),2.29-2.18 (2H, m), 1.66 (3 H, s).

Ex 277

¹H NMR (CDCl₃) delta 8.61 (1 H, dt, J=4.7, 1.6 Hz), 7.51 (1 H, dt,J=8.0, 1.5 Hz), 7.44 (1 H, s), 7.35 (1H, d, J=8.19 Hz), 7.16-7.29 (3H,m), 4.53-4.66 (2H, m), 3.46-3.64 (2H, m), 3.03 (1H, d, J=14.1 Hz), 2.85(1H, d, J=14.1 Hz), 2.49-2.75 (3 H, m), 2.13-2.40 (6H, m) 1.99-2.10 (1H,m).

MS (ESI) m/z: 456.2 (M+H)⁺.

Ex 278

¹H NMR and LCMS were identified with the Ex 277.

Ex 279

¹H NMR (CDCl₃) delta 8.61 (1H, br d, J=4.7 Hz), 7.54 (1H, d, J=8.0 Hz),7.44 (1 H, d, J=2.1 Hz), 7.34 (1H, d, J=7.7 Hz), 7.27-7.30 (1H, m),7.19-7.25 (1H, m), 4.48-4.65 (3H, m), 3.96-4.16 (2H, m), 3.89 (1 H, brs), 3.56 (1H, br d, J=13.0 Hz), 3.18 (1H, br d, J=13.1 Hz), 2.67-2.82(1H, m), 2.16-2.28 (3H, m).

MS (ESI) m/z: 454.2 (M+H)⁺.

Ex 280

¹H NMR (DMSO d6) delta 9.25 (1 H, br), 8.70 (1H, ddd, J=4.9, 1.8, 1.2Hz), 7.67 (1H, dd, J=7.9, 1.8 Hz), 7.64 (1H, d, J=1.8 Hz), 7.50-7.42(2H, m), 7.39 (1 H, d, J=6.7 Hz),5.98 (1H, s), 4.53 (1H, dd, J=15.3, 6.1Hz), 4.44 (1H, dd, J=15.3, 5.5 Hz), 3.35 (1H, d, J=16.5 Hz), 3.24 (1H,d, J=16.5 Hz), 2.82-2.64 (2H, m), 2.30-2.17 (2H, m).

Ex 282

¹H NMR (CDCl₃) delta 8.63 (1H, ddd, J=4.9, 1.8, 1.2 Hz), 7.56 (1H, ddd,J=7.9, 1.8, 1.2 Hz), 7.40 (1H, dd, J=8.6, 5.5 Hz), 7.32 (1H, dd, J=7.9,4.9 Hz), 7.23 (1 H, br), 7.20 (1H, dd, J=8.6, 2.4 Hz), 7.01 (1H, ddd,J=8.6, 7.9, 2.4 Hz), 4.63 (1H, dd, J=14.7, 6.1 Hz), 4.57 (1H, dd,J=14.7, 6.1 Hz), 4.29 (1 H, s), 2.98 (1H, d, J=16.5 Hz), 2.89 (1H, d,J=16.5 Hz), 2.82-2.27 (4H, m).

Ex 283

¹H NMR (CDCl₃) delta 8.60 (1H, ddd, J=4.9, 1.8, 1.2 Hz), 7.60 (1 H, br),7.45 (1 H, ddd, J=7.9, 1.8, 1.2 Hz), 7.44 (1H, d, J=1.8 Hz), 7.33 (1H,d, J=1.8 Hz), 7.26 (1H, m), 4.80-4.62 (4H, m), 3.78 (1H, dd, J=6.1, 5.5Hz), 3.71 (1 H, br s), 3.20 (1 H, d, J=16.5 Hz), 3.06 (1H, d, J=16.5Hz), 2.71 (1H, m), 2.40-2.37 (2H, m), 2.19 (1H, m).

Ex 284

¹H NMR (CDCl₃) delta 8.60 (1H, ddd, J=4.9, 1.8, 1.2 Hz), 7.59 (1H, br d,J=6.1 Hz), 7.45 (1H, ddd, J=7.9, 1.8, 1.2 Hz), 7.26 (1H, m), 7.18 (1H,dd, J=7.9, 2.4 Hz), 7.08 (1H, dd, J=8.6, 2.4 Hz), 4.87-4.71 (3H, m),4.65 (1H, dd, J=14.7, 6.1 Hz), 3.77 (1 H, br), 3.62 (1 H, br), 3.20 (1H,d, J=17.1 Hz), 3.06 (1H, d, J=17.1 Hz), 2.73 (1H, m), 2.43-2.37 (2H, m),2.18 (1H, m).

Ex 287

¹H NMR (CDCl₃) delta 8.62 (1H, br d, J=4.3 Hz), 7.49 (1H, dd, J=7.9, 1.2Hz), 7.45 (1H, d, J=2.4 Hz), 7.37 (1H, d, J=7.9 Hz), 7.27 (1H, dd,J=7.9, 2.4 Hz), 7.26 (1H, dd, J=7.9, 4.3 Hz), 7.18 (1H, br d,J=5.5.Hz),4.65 (1H, dd, J=14.7, 6.1 Hz), 4.58 (1H, dd, J=14.7, 6.1 Hz),3.33 (1 H, br), 3.16 (1H, d, J=13.5 Hz), 3.12 (1H, d, J=13.5 Hz), 2.68(1H, m), 2.52 (1H, m), 2.30 (1H, m), 2.18 (1H, m), 2.10 (3 H, s).

Ex 289

¹H NMR (CDCl₃) delta 8.62 (1H, ddd, J=4.9, 1.8, 1.2 Hz), 7.51 (1H, ddd,J=7.9, 1.8, 1.2 Hz), 7.41 (1H, dd, J=8.6, 6.1 Hz), 7.24 (1H, dd, J=7.9,4.9 Hz), 7.19 (1H, dd, J=7.9, 3.1 Hz), 7.19 (1 H, br), 7.00 (1H, ddd,J=8.6, 7.9, 3.1 Hz), 4.64 (1H, dd, J=14.7, 6.1 Hz), 4.58 (1H, dd,J=14.7, 6.1 Hz), 3.73 (2H, t, J=6.1 Hz), 3.71 (1 H, br), 3.23 (1H, d,J=13.4 Hz), 3.18 (1H, d, J=13.4 Hz), 2.82-2.63 (3H, m), 2.45 (1 H, m),2.31 (1H, m), 2.17 (1H, m), 1.69 (1 H, br).

TABLE 48 General Inter- Procedure mediates Structure Chemical NameSubstrate (/Amine) I-h-2-1

(5S,8R)-N-(2,4- dichlorobenzyl)-5- fluoro-8-hydroxy- 8-((methylthio)methyl)-5,6,7,8- tetrahydroquinoline- 5-carboxamide

R I-h-2-2

(5S,8S)-N-(2,4- dichlorobenzyl)-5- fluoro-8-hydroxy-8-(((2-hydroxyethyl) thio)methyl)-5,6,7,8- tetrahydroquinoline-5-carboxamide

S I-h-1-1

(5R,8S)-8-(aminomethyl)- N-(2,4-dichlorobenzyl)- 5-fluoro-8-hydroxy-5,6,7,8- tetrahydroquinoline- 5-carboxamide

J/ NH₄Cl I-h-1-2

(5S,8S)-8-(aminomethyl)- N-(2,4-dichlorobenzyl)- 5-fluoro-8-hydroxy-5,6,7,8- tetrahydroquinoline- 5-carboxamide

J/ NH₄Cl I-h-1-3

(5S,8R)-8-(aminomethyl)- N-(2,4-dichlorobenzyl)- 5-fluoro-8-hydroxy-5,6,7,8- tetrahydroquinoline- 5-carboxamide

J/ NH₄Cl

IM II-h-2-1

¹H NMR (CDCl₃) delta 8.62 (1H, ddd, J=4.3, 1.8, 1.2 Hz), 7.49 (1H, ddd,J=7.9, 1.8, 1.2 Hz), 7.45 (1H, d, J=1.8 Hz), 7.36 (1H, d, J=8.6 Hz),7.28-7.21 (3 H, m), 4.63 (1H, dd, J=14.7, 6.1 Hz), 4.58 (1H, dd, J=14.7,6.1 Hz), 4.12 (1 H, s), 2.97 (2 H, s), 2.65-2.43 (2 H, m),2.30 (1H, m),2.18 (3H, s), 2.14 (1H, m).

MS (ESI) m/z: 429.1 (M+H)⁺.

IM II-h-2-2

¹H NMR (CDCl₃) delta 8.61 (1 H, br dd, J=4.9, 1.8 Hz), 7.50 (1 H, br dd,J=7.9, 1.8 Hz), 7.45 (1H, d, J=1.8 Hz), 7.36 (1H, d, J=7.9 Hz),7.27-7.22 (2H, m), 7.20 (1 H, br), 4.64 (1H, dd, J=14.7, 6.1 Hz), 4.58(1H, dd, J=14.7, 6.1 Hz), 3.82 (1 H, br), 3.72 (2H, t, J=5.5 Hz), 3.47(1 H, s), 3.24 (1H, d, J=13.5 Hz), 3.17 (1H, d, J=13.5 Hz), 2.81-2.62(3H, m), 2.44 (1H, m), 2.30 (1H, m), 2.17 (1H, m). MS (ESI) m/z: 459.2(M+H)⁺.

IM I-h-1-1

MS (ESI) m/z: 398.1 (M+H)⁺.

IM I-h-1-2

MS (ESI) m/z: 398.1 (M+H)⁺.

IM I-h-1-3

MS (ESI) m/z: 398.1 (M+H)⁺.

Example 290(2R,5'S)-N-(2,4-dichlorobenzyl)-5′-fluoro-4-methyl-6′,7′-dihydro-5′H-spiro[morpholine-2,8′-quinoline]-5′-carboxamide

To a stirred solution of substrate (1.0 eq.) and TMAD (1.5 eq.) in THFwas added n-Bu₃P (1.5 eq.) at ambient temperature. After being stirredat ambient temperature until complete reaction, the mixture wasconcentrated under reduced pressure. The crude residue was purified bysilica gel column chromatography (EtOAc) to afford the title compound.

Ex 290

¹H NMR (DMSO d6) delta 9.22 (1 H, br s), 8.65 (1 H, dt, J=4.6, 1.6 Hz),7.60-7.70 (2H, m), 7.36-7.49 (3H, m), 4.35-4.53 (2H, m), 3.79 (1 H, td,J=11.7, 2.5 Hz), 3.61 (1H, dd, J=11.6, 3.1 Hz), 3.08 (1H, d, J=11.3 Hz),2.84 (1H, dt, J=11.8, 2.5 Hz), 2.66 (1H, br d, J=11.1 Hz), 2.52-2.58(1H, m), 2.32-2.47 (1H, m), 2.21 (3 H, s), 1.90-2.16 (3H, m).

MS (ESI) m/z: 438.1 (M+H)⁺.

The following Examples were prepared by General Procedure T (Table 49).

General Procedure T

The mixture of substrate (1.0 eq.) and 1,1′-carbonylbis-1H-imidazole(1.1 eq.) in THF was stirred at ambient temperature until completereaction. The reaction mixture was purified by silica gel columnchromatography (10% MeOH/EtOAc) to afford the following Examples.

TABLE 49 Ex- amples Structure Chemical Name Substrate 291

(5S,5′S)-N-(2,4- dichlorobenzyl)-5′- fluoro-2-oxo-6′,7′-dihydro-5′H-spiro [oxazolidine-5,8′- quinoline]-5′- carboxamide

292

(5R,5′S)-N-(2,4- dichlorobenzyl)-5′- fluoro-2-oxo-6′,7′-dihydro-5′H-spiro [oxazolidine-5,8′- quinoline]-5′- carboxamide

Ex 291

¹H NMR (DMSO d6) delta 9.27 (1 H, br s), 8.74 (1H, d, J=4.5 Hz),7.75-7.80 (2H, m), 7.62 (1H, d, J=2.1 Hz), 7.53 (1H, dd, J=8.0, 4.7 Hz),7.45 (1H, dd, J=8.4, 2.1 Hz), 7.36 (1H, d, J=8.3 Hz), 4.40 (2H, t, J=5.3Hz), 3.88 (1H, d, J=8.6 Hz), 3.53 (1H, d, J=8.4 Hz), 2.29-2.48 (5H, m).

MS (ESI) m/z: 424.1 (M+H)⁺.

Ex 292

¹H NMR (DMSO d6) delta 9.30 (1 H, br s), 8.76 (1H, d, J=4.8 Hz), 7.79 (1H, s), 7.71 (1H, d, J=8.2 Hz), 7.64 (1H, d, J=2.1 Hz), 7.54 (1H, t,J=6.2 Hz), 7.47 (1H, d, J=8.1 Hz), 7.40 (1H, d, J=8.1 Hz), 4.40-4.53(2H, m), 4.16 (1H, d, J=8.2 Hz), 3.45 (1H, d, J=8.7 Hz), 2.57-2.68 (1H,m), 2.39-2.45 (1H, m), 2.24-2.38 (2H, m). MS (ESI) m/z: 424.1 (M+H)⁺.

The following Intermediates were prepared by General Procedure U (Table50).

General Procedure U

Chloroacetyl chloride (1.1 eq.) was added dropwise to a biphasicsolution of substrate (1.0 eq.) in dichloromethane and 0.5 N aq. NaOH(2.0 eq.) at 0° C. The reaction mixture was warmed up to ambienttemperature and stirred until complete reaction. The mixture wasextracted with dichloromethane 3 times, and the combined extracts weredried over Na₂SO₄ and concentrated under reduced pressure to afford thefollowing Intermediates.

TABLE 50 Inter- mediates Structure Chemical Name Substrate I-i-1

(5R,8S)-8-((2-chloroacetamido) methyl)-N-(2,4-dichlorobenzyl)-5-fluoro-8- hydroxy-5,6,7,8- tetrahydroquinoline-5-carboxamide

I-i-2

(5S,8S)-8-((2-chloroacetamido) methyl)-N-(2,4-dichlorobenzyl)-5-fluoro-8- hydroxy-5,6,7,8- tetrahydroquinoline-5-carboxamide

I-i-3

(5S,8R)-8-((2-chloroacetamido) methyl)-N-(2,4-dichlorobenzyl)-5-fluoro-8- hydroxy-5,6,7,8- tetrahydroquinoline-5-carboxamide

IM I-i-1

MS (ESI) m/z: 474.1 (M+H)⁺.

IM I-i-2

MS (ESI) m/z: 474.1 (M+H)⁺.

IM I-i-3

MS (ESI) m/z: 474.1 (M+H)⁺.

The following Examples were prepared by General Procedure V (Table 51).

General Procedure V

To a solution of substrate (1.0 eq.) in 50% dichloromethane/2-propanolwas added portion wise tert-BuOK (4.0 eq.) at 0° C. The solution wasallowed to warm to ambient temperature and stirred until completereaction. The solvent of the reaction mixture was removed byevaporation. The crude residue was purified by silica gel columnchromatography to afford the following Examples.

TABLE 51 Ex- amples Structure Chemical Name Substrate 293

(2S,5′R)-N-(2,4- dichlorobenzyl)-5′- fluoro-5-oxo-6′,7′-dihydro-5′H-spiro [morpholine-2,8′- quinoline]-5′-carboxamide

294

(2S,5′S)-N-(2,4- dichlorobenzyl)-5′- fluoro-5-oxo-6′,7′-dihydro-5′H-spiro [morpholine-2,8′- quinoline]-5′-carboxamide

295

(2R,5′S)-N-(2,4- dichlorobenzyl)-5′- fluoro-5-oxo-6′,7′-dihydro-5′H-spiro [morpholine-2,8′- quinoline]-5′-carboxamide

Ex 293

¹H NMR (CDCl₃) delta 8.64-8.72 (1H, m), 7.54 (1H, d, J=7.5 Hz),7.27-7.47 (4H, m), 7.09-7.25 (1H, m), 4.56-4.70 (2H, m), 4.34 (1H, dd,J=12.2, 2.3 Hz), 4.11-4.23 (2H, m), 3.37 (1H, dd, J=12.2, 3.1 Hz),2.77-2.99 (1H, m), 2.40-2.51 (1H, m), 2.09-2.28 (2H, m).

MS (ESI) m/z: 438.1 (M+H)⁺.

Ex 294

¹H NMR (CDCl₃) delta 8.70 (1 H, dt, J=4.7, 1.6 Hz), 7.57 (1H, d, J=7.6Hz), 7.46 (1H, d, J=2.0 Hz), 7.19-7.35 (6H, m), 6.04 (1 H, br s),4.53-4.64 (2H, m), 4.39 (1H, d, J=16.8 Hz), 4.28 (1H, d, J=15.2 Hz),4.19 (1H, dd, J=12.5, 1.5 Hz), 3.43 (1H, dd, J=12.5, 3.9 Hz), 2.56-2.64(1H, m), 2.29-2.53 (3H, m).

MS (ESI) m/z: 438.1 (M+H)⁺.

Ex 295

¹H NMR (CDCl₃) delta 8.66 (1 H, dt, J=4.7, 1.8 Hz), 7.54 (1H, d, J=7.6Hz), 7.46 (1H, d, J=2.1 Hz), 7.39 (1H, d, J=8.2 Hz), 7.27-7.33 (2H, m),7.13-7.25 (1H, m), 6.10 (1H, br s), 4.58-4.69 (2H, m),4.34 (1H, dd,J=12.2, 2.3 Hz), 4.17 (2H, dd, J=16.8, 15.5 Hz), 3.37 (1H, dd, J=12.2,3.0 Hz) 2.77-2.95 (1H, m), 2.41-2.49 (1H, m), 2.08-2.30 (2H, m).

MS (ESI) m/z: 438.1 (M+H)⁺.

The following Examples were prepared by General Procedure W or X (Table52).

General Procedure W To a solution of substrate (1.0 eq.) indichloromethane was added mCPBA (1.05 eq.) at 0° C. The mixture wasstirred at 0° C. until complete reaction, 1:1 mixture of aq. Na₂S₂O₃ andaq. NaHCO₃ was added to the mixture. The resulting mixture was extractedwith CH₂Cl₂ and the extract was dried over Na₂SO₄. The extract wasconcentrated in vacuo, and the resulting residue was purified by silicagel column chromatography and preparative HPLC to afford the followingExamples.

General Procedure X

To a solution of substrate (1.0 eq.) in dichloromethane was added mCPBA(2.5 eq.) at 0° C. The mixture was stirred at 0° C. until completereaction, 1:1 mixture of aq. Na₂ S₂O₃ and aq. NaHCO₃ was added to themixture. The resulting mixture was extracted with CH₂Cl₂ and the extractwas dried over Na₂SO₄. The extract was concentrated in vacuo, and theresulting residue was purified by silica gel column chromatography andpreparative HPLC to afford the following Examples.

TABLE 52 Ex- General amples Structure Chemical Name Substrate Procedure296

(5S,8S)-N-(2-chloro-4- fluorobenzyl)-5-fluoro- hydroxy-8-((methylsulfinyl) methyl)-5,6,7,8- tetrahydroquinoline- 5-carboxamide

W 297

(5S,8R)-N-(2,4- dichlorobenzyl)-5- fluoro-8-hydroxy-8-((methylthio)methyl)- 5,6,7,8- tetrahydroquinoline- 5-carboxamide

X 298

(5S,8S)-N-(2,4- dichlorobenzyl)-5- fluoro-8-hydroxy-8- ((methylsulfonyl)methyl)-5,6,7,8- tetrahydroquinoline- 5-carboxamide

X 299

(5S,8S)-N-(2-chloro-4- fluorobenzyl)-5-fluoro-8- hydroxy-8-((methylsulfonyl) methyl)-5,6,7,8- tetrahydroquinoline- 5-carboxamide

X 300

(5S,8S)-N-(2,4- dichlorobenzyl)-5- fluoro-8-hydroxy-8-(((2-hydroxyethyl) sulfonyl)methyl)-5,6,7,8- tetrahydroquinoline-5-carboxamide

X 301

(5S,8S)-N-(2-chloro-4- fluorobenzyl)-5-fluoro-8- hydroxy-8-(((2-hydroxyethyl) sulfonyl)methyl)- 5,6,7,8- tetrahydroquinoline-5-carboxamide

X

TABLE 53 LC MS Examples Method tR (min) [M + H]⁺ 296 D 1.29 429.0 297 D1.58 461.0 298 D 1.56 461.0 299 D 1.44 445.0 300 D 1.47 491.0 301 D 1.36475.0

Ex 296

¹H NMR (CDCl₃) delta 8.65-8.60 (1H, m), 7.56-7.51 (1H, m), 7.43-7.37(1H, m), 7.31-7.26 (1H, m), 7.24-7.17 (2H, m), 7.02-6.97 (1H, m),4.68-4.54 (2H, m), 4.08 (1 H, br), 3.77 (0.5 H, d, J=12.8 Hz), 3.58 (0.5H, d, J=13.5 Hz), 3.35 (0.5 H, d, J=12.8 Hz), 3.11 (0.5 H, d, J=13.5Hz), 2.86 (0.5 H, m), 2.74 (1.5 H, s), 2.69 (1.5 H, s), 2.69 (0.5 H, m),2.61-2.46 (2H, m), 2.32-2.19 (1H, m).

Ex 297

¹H NMR (CDCl₃) delta 8.62 (1H, ddd, J=4.9, 1.8, 1.2 Hz), 7.57 (1H, dd,J=7.9, 1.2 Hz), 7.45 (1H, d, J=1.8 Hz), 7.35-7.31 (2H, m), 7.27 (1H, dd,J=7.9, 4.9 Hz), 7.19 (1H, br d, J=4.9 Hz), 4.62 (1H, dd, J=14.7, 6.1Hz), 4.573 (1 H, s), 4.566 (1H, dd, J=14.7, 6.1 Hz), 3.55 (1H, d, J=16.5Hz), 3.51 (1H, d, J=16.5 Hz), 3.14 (3 H, s), 3.07 (1H, m), 2.63 (1H, m),2.40 (1H, m), 2.18 (1H, m).

Ex 298

¹H NMR (CDCl₃) delta 8.62 (1H, br d, J=4.9 Hz), 7.55 (1H, dd, J=7.9, 1.2Hz), 7.45 (1H, d, J=1.8 Hz), 7.35 (1H, d, J=7.9 Hz), 7.30 (1H, dd,J=7.9, 4.9 Hz), 7.26 (1H, dd, J=7.9, 1.8 Hz), 7.21 (1 H, br), 4.64 (1H,dd, J=14.7, 6.1 Hz), 4.57 (1H, dd, J=14.7, 6.1 Hz), 4.12 (1H, d, J=15.3Hz), 4.03 (1 H, br), 3.37 (1H, d, J=15.3 Hz), 3.11 (3 H, s), 2.79-2.64(3H, m), 2.24 (1H, m).

Ex 299

¹H NMR (CDCl₃) delta 8.62 (1H, br d, J=4.9 Hz), 7.55 (1H, d, J=7.9 Hz),7.40 (1 H, dd, J=8.6, 6.1 Hz), 7.30 (1H, dd, J=7.9, 4.9 Hz), 7.21 (1 H,br), 7.19 (1H, dd, J=8.6, 2.4 Hz), 7.00 (1H, ddd, J=8.6, 7.9, 1.8 Hz),4.64 (1H, dd, J=14.7, 6.1 Hz), 4.57 (1H, dd, J=14.7, 6.1 Hz), 4.12 (1H,d, J=15.3 Hz), 4.02 (1H, br), 3.37 (1H, d, J=15.3 Hz), 3.11 (3 H, s),2.79-2.64 (3H, m), 2.24 (1H, m).

Ex 300

¹H NMR (CDCl₃) delta 8.58 (1 H, br s), 7.53 (1H, d, J=7.9 Hz), 7.44 (1H, br s), 7.34-7.22 (4H, m), 4.72 (1 H, br), 4.62 (1H, dd, J=15.3, 6.1Hz), 4.34 (1H, dd, J=15.3, 6.1 Hz), 4.34 (1H, d, J=15.3 Hz), 4.09 (2 H,br), 3.62 (1H, m), 3.43 (1H, d, J=15.3 Hz), 3.42 (1 H, br s), 3.25 (1H,m), 2.77-2.66 (3H, m), 2.21 (1H, m).

Ex 301

¹H NMR (CDCl₃) delta 8.60 (1 H, br s), 7.54 (1H, d, J=7.9 Hz), 7.39 (1H,dd, J=7.9, 6.1 Hz), 7.29 (1H, m), 7.26 (1 H, br), 7.19 (1 H, dd, 8.6,2.4 Hz), 7.00 (1 H, dd, J=8.6, 7.9 Hz), 4.63 (1H, dd, J=14.7, 6.1 Hz),4.55 (1H, dd, J=14.7, 6.1 Hz), 4.54 (1 H, br), 4.34 (1H, d, J=15.3 Hz),4.12 (2 H, br), 3.62 (1H, m), 3.46 (1H, d, J=15.3 Hz), 3.44 (1 H, br s),3.29 (1H, m), 3.03-2.71 (3H, m), 2.22 (1H, m).

The following Examples were prepared by General Procedure Y or Z (Table54).

General Procedure Y

To stirred solution of the substrate (1.0 eq.) in MeOH-tert-BuOH-water(1:1:1) was added AD-Mix alpha and/or beta (4 times weight of substrate)at ambient temperature. The mixture was stirred at room temperatureuntil complete reaction, aq. Na₂ S₂O₃ was added to the mixture and thenthe mixture was stirred for 2 h. The mixture was extracted with CH₂Cl₂twice and the extracts were combined. The extracts were dried overNa₂SO₄ and concentrated in vacuo. The resulting residue was purified andeach diastereo isomer was separated by silica gel column chromatographyto afford the following Examples.

General Procedure Z

A mixture of substrate (1.0 eq.) and 2 N aq. NaOH (15.0 eq.) in 50%1,4-dioxane-water (0.02 M) was heated at 65° C. until complete reaction.The mixture was extracted with CH₂Cl₂ twice and the extracts werecombined. The extracts were dried over Na₂SO₄ and concentrated in vacuoto afford a glass. The residual glass was purified by silica gel columnchromatography and preparative HPLC to afford following Examples.

TABLE 54 Ex- General amples Structure Chemical Name Substrate Procedure302

(5R,8R)-N-(2,4- dichlorobenzyl)- 5-fluoro-8- hydroxy-8- (hydroxymethyl)-5,6,7,8- tetrahydroquinoline- 5-carboxamide

Y 303

(5R,8S)-N-(2,4- dichlorobenzyl)- 5-fluoro-8- hydroxy-8- (hydroxymethyl)-5,6,7,8- tetrahydroquinoline- 5-carboxamide 304

(5S,8S)-N-(2,4- dichlorobenzyl)- 5-fluoro-8- hydroxy-8- (hydroxymethyl)-5,6,7,8- tetrahydroquinoline- 5-carboxamide

Y 305

(5S,8R)-N-(2,4- dichlorobenzyl)- 5-fluoro-8- hydroxy-8- (hydroxymethyl)-5,6,7,8- tetrahydroquinoline- 5-carboxamide 306

(5S,8S)-N- (2-chloro-4- fluorobenzyl)- 5-fluoro- 8-hydroxy-8-(hydroxymethyl)- 5,6,7,8- tetrahydroquinoline- 5-carboxamide

Y 307

(5S,8R)-N- (2-chloro-4- fluorobenzyl)- 5-fluoro-8- hydroxy-8-(hydroxymethyl)- 5,6,7,8- tetrahydroquinoline- 5-carboxamide 308

(5S,8S)-5-fluoro-8- hydroxy-8- (hydroxymethyl)- N-(2,3,4-trifluorobenzyl)- 5,6,7,8- tetrahydroquinoline- 5-carboxamide

Y 309

(5S,8R)-5-fluoro-8- hydroxy-8- (hydroxymethyl)- N-(2,3,4-trifluorobenzyl)- 5,6,7,8- tetrahydroquinoline- 5-carboxamide 310

(5S,8S)-N- (2,4-dichloro- 6-fluorobenzyl)- 5-fluoro- 8-hydroxy-8-(hydroxymethyl)- 5,6,7,8- tetrahydroquinoline- 5-carboxamide

Y 311

(5S,8R)-N- (2,4-dichloro- 6-fluorobenzyl)- 5-fluoro- 8-hydroxy-8-(hydroxymethyl)- 5,6,7,8- tetrahydroquinoline- 5-carboxamide 312

(5S,8S)-N-(2- chloro-3,4- difluorobenzyl)-5- fluoro-8-hydroxy-8-(hydroxymethyl)- 5,6,7,8- tetrahydroquinoline- 5-carboxamide

Y 313

(5S,8R)-N-(2- chloro-3,4- difluorobenzyl)- 5-fluoro- 8-hydroxy-8-(hydroxymethyl)- 5,6,7,8- tetrahydroquinoline- 5-carboxamide 314

(5S,8S)-N- (4-chloro-2- fluorobenzyl)- 5-fluoro-8- hydroxy-8-(hydroxymethyl)- 5,6,7,8- tetrahydroquinoline- 5-carboxamide

Y 315

(5S,8R)-N- (4-chloro-2- fluorobenzyl)- 5-fluoro-8- hydroxy-8-(hydroxymethyl)- 5,6,7,8- tetrahydroquinoline- 5-carboxamide 316

(5S,8S)-N- (2,4-dichloro- 6-(hydroxymethyl) benzyl)-5-fluoro-8-hydroxy-8- (hydroxymethyl)- 5,6,7,8- tetrahydroquinoline- 5-carboxamide

Z 317

(5S,8S)-N-(2-chloro-4- fluoro-6- (hydroxymethyl) benzyl)-5-fluoro-8-hydroxy-8- (hydroxymethyl)- 5,6,7,8- tetrahydroquinoline- 5-carboxamide

Z 318

(5S,8S)-N-(2,4- difluorobenzyl)-5- fluoro-8-hydroxy-8- (hydroxymethyl)-5,6,7,8- tetrahydroquinoline- 5-carboxamide

Z 319

(5S,8S)-N- (2,4-dichloro- 3-fluorobenzyl)- 5-fluoro- 8-hydroxy-8-(hydroxymethyl)- 5,6,7,8- tetrahydroquinoline- 5-carboxamide

Z 320

(5S,8S)-N- (2,3-dichloro- 4-fluorobenzyl)- 5-fluoro- 8-hydroxy-8-(hydroxymethyl)- 5,6,7,8- tetrahydroquinoline- 5-carboxamide

Z 321

(5S,8S)-N- (2-chloro-4,6- difluorobenzyl)- 5-fluoro- 8-hydroxy-8-(hydroxymethyl)- 5,6,7,8- tetrahydroquinoline- 5-carboxamide

Z 322

(5S,8S)-N- (4-chloro-2,3- difluorobenzyl)- 5-fluoro- 8-hydroxy-8-(hydroxymethyl)- 5,6,7,8- tetrahydroquinoline- 5-carboxamide

Z 323

(5S,8S)-N- (3-chloro-2,4- difluorobenzyl)- 5-fluoro- 8-hydroxy-8-(hydroxymethyl)- 5,6,7,8- tetrahydroquinoline- 5-carboxamide

Z 324

(5S,8S)-N- (4-chloro-2,6- difluorobenzyl)- 5-fluoro- 8-hydroxy-8-(hydroxymethyl)- 5,6,7,8- tetrahydroquinoline- 5-carboxamide

Z 325

(5S,8S)-N-(2,4- dichlorobenzyl)- 5-fluoro-8-hydroxy- 8-(hydroxymethyl)-3-methyl-5,6,7,8- tetrahydroquinoline- 5-carboxamide

Z 326

(5S,8S)-N-((R)-1-(2,4- dichlorophenyl) ethyl)-5- fluoro-8-hydroxy-8-(hydroxymethyl)- 5,6,7,8- tetrahydroquinoline- 5-carboxamide

Z 327

(5S,8S)-N-((R)-1-(2- chloro-4-fluorophenyl) ethyl)-5-fluoro-8-hydroxy-8- (hydroxymethyl)- 5,6,7,8- tetrahydroquinoline-5-carboxamide

Z 328

(5S,8R)-N-((R)-1-(2- chloro-4-fluorophenyl) ethyl)-5-fluoro-8-hydroxy-8- (hydroxymethyl)- 5,6,7,8- tetrahydroquinoline-5-carboxamide

Z 329

(5S,8S)-N-((3,5- dichloropyridin-2- yl)methyl)-5- fluoro-8-hydroxy-8-(hydroxymethyl)- 5,8,7,8- tetrahydroquinoline- 5-carboxamide

Z 330

(5S,8S)-N-(2,4- dichlorophenethyl)- 5-fluoro-8- hydroxy-8-(hydroxymethyl)- 5,6,7,8- tetrahydroquinoline- 5-carboxamide

Z 331

(5S,8S)-N- ((trans)-2-(2,4- dichlorophenyl) cyclopropyl)-5-fluoro-8-hydroxy- 8-(hydroxymethyl)- 5,6,7,8- tetrahydroquinoline-5-carboxamide

Z 332

(5S,8S)-N-((4-(2,4- dichlorophenyl) tetrahydro- 2H-pyran-4-yl)methyl)-5- fluoro-8-hydroxy-8- (hydroxymethyl)- 5,6,7,8-tetrahydroquinoline- 5-carboxamide

Z

TABLE 55 LC MS Examples Method tR (min) [M + H]⁺ 302 C 1.42 398.8 303 C1.41 398.8 304 C 1.41 398.9 305 C 1.42 398.9 306 C 1.31 382.9 307 C 1.30382.9 308 C 1.27 384.9 309 C 1.27 385.0 310 C 1.40 416.8 311 C 1.40416.8 312 C 1.34 401.0 313 C 1.34 401.0 314 C 1.32 382.8 315 C 1.32382.8 316 C 1.28 428.9 317 D 1.18 413.0 318 C 1.22 366.9 319 D 1.47417.0 320 D 1.46 417.0 321 D 1.33 401.0 322 D 1.40 401.0 323 D 1.38401.0 324 D 1.36 401.0 325 D 1.54 413.1 326 D 1.54 413.1 327 D 1.41397.1 328 D 1.42 397.1 329 D 1.31 400.0 330 D 1.51 413.0 331 D 1.59425.0 332 D 1.47 483.0

Ex 302

¹H NMR (CDCl₃) delta 8.54 (1 H, br dd, J=4.9, 1.8 Hz), 7.53 (1 H, br dd,J=7.9, 1.8 Hz), 7.45 (1H, d, J=1.8 Hz), 7.38 (1H, d, J=8.6 Hz), 7.29(1H, dd, J=7.9, 4.9 Hz), 7.20-7.14 (2H, m), 5.00 (1 H, br), 4.66 (1H,dd, J=14.7, 6.1 Hz), 4.60 (1H, dd, J=14.7, 6.1 Hz), 3.99 (1H, d, J=11.6Hz), 3.76-3.64 (2H, m), 2.88 (1H, m), 2.24-1.99 (3H, m).

Ex 303

¹H NMR (DMSO d6) delta 9.16 (1 H, br), 8.64 (1H, br d, J=4.9 Hz), 7.66(1 H, d, J=7.9 Hz),7.62 (1H, d, J=2.4 Hz), 7.46 (1H, dd, J=7.9, 2.4 Hz),7.39 (1H, dd, J=7.9, 4.9 Hz), 7.36 (1 H, J=7.9 Hz), 4.93 (1 H, s), 4.75(1 H, br), 4.44 (1H, dd, J=15.9, 6.1 Hz), 4.38 (1H, dd, J=15.9, 6.1 Hz),3.68 (1H, dd, J=11.0, 6.1 Hz), 3.56 (1 H, dd, J=11.0, 4.3 Hz), 2.54-2.22(3H, m), 1.87 (1H, m).

Ex 304

¹H NMR was identified with the Example 302.

Ex 305

¹H NMR was identified with the Example 303.

Ex 306

¹H NMR (CDCl₃) delta 8.54 (1 H, br dd, J=4.5, 1.8 Hz), 7.53 (1 H, br dd,J=7.9, 1.8 Hz), 7.43 (1H, dd, J=8.6, 6.1 Hz), 7.28 (1 H, br dd, J=4.9,1.2 Hz), 7.19 (1H, dd, J=8.6, 2.4 Hz),7.17 (1H, br), 7.00 (1H, dt,J=7.9, 2.4 Hz),5.01 (1H, br d, J=9.8 Hz), 4.66 (1H, dd, J=14.7, 6.1 Hz),4.60 (1H, dd, J=14.7, 5.5 Hz), 3.99 (1H, d, J=11.6 Hz), 3.79-3.63 (2H,m), 2.88 (1H, m), 2.36-1.99 (3H, m).

Ex 307

¹H NMR (CDCl₃) delta 8.57 (1 H, br dd, J=4.3, 1.8 Hz), 7.56 (1H, d,J=7.9 Hz), 7.39 (1H, dd, J=8.5, 6.1 Hz), 7.28 (1H, dd, J=7.9, 4.3 Hz),7.19 (1H, dd, J=8.5, 2.4 Hz), 7.16 (1 H, br), 6.99 (1H, ddd, J=8.5, 7.9,2.4 Hz), 4.62 (1H, dd, J=14.7, 6.1 Hz), 4.55 (1H, dd, J=14.7, 6.1 Hz),4.01 (1 H, br), 3.85 (1H, d, J=11.6 Hz), 3.79 (1 H, br), 3.71 (1H, d,J=11.6 Hz), 2.54-2.36 (3H, m), 2.02 (1H, m).

Ex 308

¹H NMR (CDCl₃) delta 8.54 (1 H, br dd, J=4.5, 1.8 Hz), 7.53 (1 H, br dd,J=7.9, 1.8 Hz), 7.30 (1H, dd, J=7.9, 4.9 Hz), 7.20 (1H, br d, J=4.9 Hz),7.13 (1H, m), 6.98 (1H, m),5.02 (1H, br), 4.64 (1H, dd, J=14.7, 6.1 Hz),4.57 (1H, dd, J=14.7, 6.1 Hz), 3.97 (1H, d, J=11.6 Hz), 3.85 (1 H, br),3.68 (1H, d, J=11.6 Hz), 2.87 (1 H, m), 2.23-1.99 (3H, m).

Ex 309

¹H NMR (CDCl₃) delta 8.57 (1 H, br dd, J=4.9, 1.2 Hz), 7.56 (1 H, br dd,J=7.9, 1.2 Hz), 7.29 (1H, dd, J=7.9, 4.9 Hz), 7.16 (1 H, br), 7.09 (1H,m), 6.97 (1H, m), 4.60 (1H, dd, J=15.3, 6.1 Hz), 4.53 (1H, dd, J=15.3,6.1 Hz), 4.01 (1H, br), 3.84 (1 H, d, J=11.0 Hz), 3.82 (1 H, br), 3.71(1H, d, J=11.6 Hz), 2.44-2.04 (3H, m), 2.04 (1H, m).

Ex 310

¹H NMR (CDCl₃) delta 8.53 (1H, m), 7.56 (1H, d, J=7.9 Hz), 7.33-7.28(2H, m), 7.11 (1H, dd, J=9.2, 1.8 Hz), 7.02 (1 H, br), 5.01 (1 H, br),4.78 (1H, dd, J=14.7, 5.5 Hz), 4.66 (1H, dd, J=14.7, 5.5 Hz), 3.97 (1H,d, J=11.6 Hz), 3.76 (1 H, br), 3.68 (1H, d, J=11.6 Hz), 2.88 (1H, m),2.23-1.98 (3H, m).

Ex 311

¹H NMR (CDCl₃) delta 8.56 (1H, dd, J=4.9, 1.2 Hz), 7.57 (1H, dd, J=7.9,1.2 Hz), 7.29-7.27 (2H, m), 7.11 (1H, dd, J=9.2, 2.4 Hz), 7.04 (1 H,br), 4.73 (1 H, dd, J=14.7, 6.1 Hz), 4.63 (1H, dd, J=14.7, 5.5 Hz), 4.00(1 H, br s), 3.84 (1H, d, J=11.6 Hz), 3.79 (1 H, br), 3.70 (1H, d,J=11.6 Hz), 2.52-2.37 (3H, m), 2.02 (1H, m).

Ex 312

¹H NMR (CDCl₃) delta 8.53 (1H, dd, J=4.9, 1.8 Hz), 7.52 (1H, ddd, J=7.9,1.8, 1.2 Hz), 7.29 (1H, dd, J=7.9, 4.9 Hz), 7.25-7.08 (3H, m), 4.99 (1H,br d, J=10.4 Hz),4.67 (1H, dd, J=14.7, 6.1 Hz), 4.62 (1H, dd, J=14.7,5.5 Hz), 3.99 (1H, d, J=10.4 Hz), 3.71 (1 H, br s), 3.67 (1H, d, J=10.4Hz), 2.88 (1H, m), 2.24-1.99 (3H, m).

Ex 313

¹H NMR (CDCl₃) delta 8.57 (1H, ddd, J=4.9, 1.8, 1.2 Hz), 7.56 (1H, dd,J=7.9, 1.8 Hz), 7.29 (1H, dd, J=7.9, 4.9 Hz), 7.19-7.08 (3H, m), 4.63(1H, dd, J=14.7, 6.1 Hz),4.57 (1H, dd, J=14.7, 5.5 Hz), 3.99 (1H, s),3.85 (1H, d, J=11.0 Hz), 3.76 (1 H, br s), 3.72 (1H, d, J=11.0 Hz),2.50-2.40 (3H, m), 2.03 (1H, m).

Ex 314

¹H NMR (CDCl₃) delta 8.53 (1 H, br dd, J=4.9, 1.8 Hz), 7.53 (1 H, br dd,J=7.9, 1.8 Hz), 7.33 (1H, t, J=7.9 Hz), 7.29 (1H, dd, J=7.9, 4.9 Hz),7.27-7.10 (2H, m), 7.15 (1H, d, J=7.9 Hz), 5.02 (1 H, br), 4.63 (1H, dd,J=14.7, 6.1 Hz), 4.54 (1H, dd, J=14.7, 6.1 Hz), 3.98 (1H, d, J=11.6 Hz),3.82 (1 H, br), 3.68 (1H, d, J=11.6 Hz), 2.87 (1H, m), 2.18 (1H, m),2.09-1.99 (2H, m).

Ex 315

¹H NMR (CDCl₃) delta 8.56 (1 H, br dd, J=4.9, 1.8 Hz), 7.55 (1H, d,J=7.9 Hz), 7.35-7.27 (2H, m), 7.18-7.09 (3H, m), 4.57 (1H, dd, J=14.7,6.1 Hz), 4.50 (1H, dd, J=14.7, 6.1 Hz), 4.06 (1 H, br), 3.83 (2H, d,J=11.0 Hz), 3.70 (1H, d, J=11.0 Hz), 2.52-2.34 (3H, m), 2.04 (1H, m).

Ex 316

¹H NMR (CDCl₃) delta 8.51 (1 H, br dd, J=4.9, 1.8 Hz), 7.58 (1H, br d,J=5.5 Hz), 7.46 (1 H, br dd, J=7.9, 1.8 Hz), 7.43 (1H, d, J=2.4 Hz),7.34 (1H, d, J=2.4 Hz), 7.26 (1H, dd, J=7.9, 4.9 Hz), 5.03 (1 H, br),4.82-4.64 (4H, m), 3.97 (1H, d, J=11.0 Hz), 3.87 (2 H, br), 3.66 (1H, d,J=11.0 Hz), 2.81 (1H, m), 2.19-1.95 (3H, m).

Ex 317

¹H NMR (CDCl₃) delta 8.52 (1H, br d, J=4.9 Hz), 7.56 (1 H, br), 7.46(1H, dd, J=7.9, 1.8 Hz), 7.25 (1H, dd, J=7.9, 4.9 Hz), 7.17 (1H, dd,J=8.6, 2.4 Hz), 7.10 (1H, dd, J=8.6, 2.4 Hz), 5.06 (1 H, br), 4.82-4.62(4H, m), 3.98 (1H, d, J=11.0 Hz), 3.81 (1 H, br), 3.66 (1H, d, J=11.0Hz), 2.81 (1H, m), 2.11 (1H, m), 2.07-1.96 (2H, m), 1.65 (1 H, br).

Ex 318

¹H NMR (CDCl₃) delta 8.53 (1 H, br dd, J=4.9, 1.8 Hz), 7.53 (1H, d,J=7.9 Hz), 7.34 (1H, m), 7.28 (1H, dd, J=7.9, 4.9 Hz), 7.16 (1 H, br),6.90-6.85 (2H, m), 5.30 (1H, br), 4.62 (1H, dd, J=14.7, 6.1 Hz), 4.53(1H, dd, J=14.7, 6.1 Hz), 3.97 (1H, d, J=11.6 Hz), 3.87 (1 H, br), 3.67(1H, d, J=11.6 Hz), 2.88 (1H, m), 2.23-1.99 (3 H, m).

Ex 319

¹H NMR (CDCl₃) delta 8.54 (1 H, br dd, J=4.9, 1.8 Hz), 7.54 (1 H, br dd,J=7.9, 1.8 Hz), 7.33 (1H, dd, J=8.6, 6.7 Hz), 7.30 (1H, dd, J=7.9, 4.9Hz), 7.23 (1 H, br), 7.20 (1H, dd, J=8.6, 1.8 Hz), 4.99 (1H, br d, J=9.2Hz), 4.68 (1H, dd, J=14.7, 6.1 Hz),4.63 (1H, dd, J=14.7, 6.1 Hz), 4.00(1H, d, J=11.0 Hz), 3.77 (1H, br s), 3.68 (1 H, br), 2.87 (1H, m),2.24-1.99 (3H, m).

Ex 320

¹H NMR (CDCl₃) delta 8.54 (1 H, br dd, J=4.9, 1.8 Hz), 7.53 (1 H, br dd,J=7.9, 1.8 Hz), 7.37 (1H, dd, J=8.6, 5.5 Hz), 7.29 (1H, dd, J=7.9, 4.9Hz), 7.21 (1 H, br d J=6.1 Hz),7.11 (1H, dd, J=8.6, 7.9 Hz), 5.00 (1H,br), 4.68 (1H, dd, J=15.3, 6.1 Hz), 4.63 (1H, dd, J=14.7, 6.1 Hz), 3.99(1H, d, J=11.0 Hz), 3.74 (1H, br s), 3.68 (1H, d, J=11.0 Hz), 2.87 (1H,m), 2.24-1.99 (3H, m).

Ex 321

¹H NMR (CDCl₃) delta 8.54 (1 H, br dd, J=4.9, 1.8 Hz), 7.57 (1 H, br dd,J=7.9, 1.8 Hz), 7.29 (1H, dd, J=7.9, 4.9 Hz), 7.05 (1H, ddd, J=7.9, 2.4,1.8 Hz), 6.99 (1 H, br), 6.85 (1H, ddd, J=9.8, 8.6, 2.4 Hz), 4.80 (1 H,br), 4.77 (1H, dd, J=14.7, 6.1 Hz),4.66 (1H, dd, J=14.7, 6.1 Hz), 3.98(1H, d, J=11.6 Hz), 3.74 (1H, br), 3.68 (1 H, d, J=11.6 Hz), 2.88 (1H,m), 2.23-1.99 (3H, m).

Ex 322

¹H NMR (CDCl₃) delta 8.55 (1 H, br dd, J=4.9, 1.8 Hz), 7.54 (1 H, br dd,J=7.9, 1.8 Hz), 7.30 (1H, dd, J=8.0, 5.5 Hz), 7.21-7.10 (3H, m), 5.00 (1H, br), 4.66 (1H, dd, J=14.7, 6.9 Hz), 4.59 (1H, dd, J=14.7, 6.9 Hz),3.99 (1H, d, J=11.6 Hz), 3.78 (1 H, br), 3.68 (1H, d, J=11.6 Hz), 2.87(1H, m), 2.24-1.99 (3H, m).

Ex 323

¹H NMR (CDCl₃) delta 8.55 (1 H, br dd, J=4.3, 1.8 Hz), 7.53 (1 H, br dd,J=7.9, 1.8 Hz), 7.34-7.28 (2H, m), 7.16 (1H, m), 6.99 (1 H, dt, J=8.6,1.8 Hz), 5.01 (1 H, br),4.64 (1H, dd, J=14.7, 6.1 Hz), 4.50 (1H, dd,J=14.7, 6.1 Hz), 3.99 (1H, d, J=11.6 Hz), 3.77 (1 H, br), 3.68 (1H, d,J=11.6 Hz), 2.87 (1H, m), 2.24-1.99 (3H, m).

Ex 324

¹H NMR (CDCl₃) delta 8.54 (1H, ddd, J=4.3, 1.8, 1.2 Hz), 7.55 (1H, ddd,J=7.9, 1.8, 1.2 Hz), 7.30 (1 H, dd J=7.9, 4.9 Hz), 7.02 (1 H, br), 7.01(2H, d, J=7.3 Hz), 5.00 (1 H, br), 4.70 (1H, dd, J=14.7, 6.1 Hz), 4.60(1H, dd, J=14.7, 5.5 Hz), 3.98 (1 H, d, J=11.6 Hz), 3.71 (1 H, br), 3.68(1H, d, J=11.6 Hz), 2.87 (1H, m), 2.22-1.98 (3H, m).

Ex 325

¹H NMR (CDCl₃) delta 8.35 (1 H, s), 7.46 (1H, d, J=2.4 Hz), 7.40 (1 H, dJ=7.9 Hz), 7.28-7.25 (2H, m), 7.19 (1H, br d, J=5.5 Hz), 5.10 (1 H, br),4.67 (1H, dd, J=14.7, 6.1 Hz), 4.60 (1H, dd, J=14.7, 6.1 Hz), 3.97 (1H,d, J=11.6 Hz), 3.67 (1H, d, J=11.6 Hz), 3.65 (1 H, br s), 2.87 (1H, m),2.27 (3 H, s), 2.22-1.96 (3H, m).

Ex 326

¹H NMR (CDCl₃) delta 8.54 (1 H, br dd, J=4.3, 1.8 Hz), 7.47 (1H, ddd,J=7.9, 1.8, 1.2 Hz),7.44 (1H, d J=1.8 Hz),7.37 (1H, d, J=8.6 Hz), 7.30(1H, dd, J=8.6, 1.8 Hz), 7.25 (1H, dd, J=7.9, 4.3 Hz), 7.12 (1H, dd,J=6.7, 6.1 Hz), 5.46 (1 H, dq, J=7.3, 6.7 Hz), 3.98 (1H, d, J=11.6 Hz),3.75 (1 H, br), 3.69 (1H, d, J=11.6 Hz), 3.48 (1H, d, J=1.8 Hz), 2.88(1H, m), 2.26-2.01 (3H, m), 1.59 (3H, d, J=7.3 Hz).

Ex 327

¹H NMR (CDCl₃) delta 8.51 (1H, ddd, J=4.3, 1.8, 1.2 Hz), 7.48 (1H, ddd,J=7.9, 1.8, 1.2 Hz), 7.41 (1H, dd, J=8.6, 6.1 Hz), 7.24 (1H, dd, J=7.9,4.3 Hz), 7.18 (1H, dd, J=8.6, 2.4 Hz), 7.14 (1 H, br), 7.04 (1H, ddd,J=8.6, 7.9, 2.4 Hz), 5.48 (1 H, dq, J=7.3, 6.7 Hz), 3.98 (1H, d, J=11.6Hz), 3.69 (1H, d, J=11.6 Hz), 2.90 (1H, m), 2.48 (2 H, br), 2.26-1.99(3H, m), 1.60 (3H, d, J=7.3 Hz).

Ex 328

¹H NMR (CDCl₃) delta 8.53 (1H, ddd, J=4.9, 1.8, 1.2 Hz), 7.53 (1H, ddd,J=7.9, 1.8, 1.2 Hz), 7.38 (1H, dd, J=8.6, 6.1 Hz), 7.24 (1H, dd, J=7.9,4.9 Hz), 7.16 (1H, dd, J=8.6, 3.1 Hz),7.10 (1H, br), 7.02 (1H, dt,J=8.6, 3.1 Hz),5.39 (1H, m),4.00 (1 H, br), 3.83 (1H, d, J=11.6 Hz),3.69 (1H, d, J=11.6 Hz), 2.56-2.38 (3H, m), 2.03 (1H, m), 1.66 (1 H,br), 1.59 (3H, d, J=7.3 Hz).

Ex 329

¹H NMR (CDCl₃) delta 8.55 (1H, br d, J=4.3 Hz), 8.48 (1H, d, J=2.4 Hz),8.08 (1 H, br d, J=4.3 Hz), 7.79 (1H, dd, J=7.9, 1.8 Hz), 7.78 (1H, d,J=2.4 Hz), 7.31 (1 H, dd, J=7.9, 4.3 Hz), 4.83 (1H, dd, J=18.3, 4.9 Hz),4.70 (1H, dd, J=18.3, 4.3 Hz), 4.02 (1H, d, J=11.6 Hz), 3.72 (1H, d,J=11.6 Hz), 2.94 (1H, m), 2.32-2.02 (3H, m). The signals due to OH werenot observed.

Ex 330

¹H NMR (CDCl₃) delta 8.54 (1 H, br dd, J=4.9, 1.8 Hz), 7.42 (1H, d,J=1.8 Hz), 7.36 (1 H, br dd, J=7.9, 1.8 Hz), 7.28-7.20 (3H, m), 6.86(1H, br d, J=5.5 Hz), 5.00 (1 H, br), 3.98 (1H, d, J=11.0 Hz), 3.77-3.62(2H, m), 3.68 (1H, d, J=11.0 Hz), 3.48 (1 H, s), 3.07-3.03 (2H, m), 2.83(1H, m), 2.18-1.98 (3H, m).

Ex 331

¹H NMR (CDCl₃) delta 8.57-8.54 (1H, m), 7.63 (1H, br d, J=7.9, 1.8 Hz),7.39 (1 H, d, J=1.8 Hz), 7.33 (1H, dd, J=7.9, 4.9 Hz), 7.20-7.11 (2H,m), 7.03 (1 H, br), 4.90 (1 H, br), 3.99 (1H, d, J=11.6 Hz), 3.74 (1 H,br), 3.70 (1H, d, J=11.6 Hz), 3.08 (1H, m), 2.90 (1H, m), 2.3-2.01 (4H,m), 1.42-1.29 (2H, m).

The following Intermediates were prepared by General Procedure AA (Table56).

General Procedure AA

To a stirred solution of substrate (1.0 eq.), iodomethane (15 eq.), andsilver(I)oxide (10 eq.) in THF was added one drop of dimethyl sulfide atambient temperature in the dark. The mixture was stirred at roomtemperature for 1 h, and then heated to 50° C. After being stirred at50° C. until complete reaction, the mixture was cooled to roomtemperature. The insoluble material was removed by filtration, theresulting filtrate was concentrated in vacuo. The residue was purifiedby silica gel column chromatography to afford following Intermediates.

TABLE 56 Intermediates Structure Chemical Name Substrate II-s-1

(5R,8S)-methyl 5-fluoro-8- methoxy-5,6,7,8- tetrahydroquinoline-5-carboxylate

II-s-2

(5S,8S)-methyl 5-fluoro-8-methoxy-5,6,7,8- tetrahydroquinoline-5-carboxylate

II-s-3

(5S,8R)-methyl 5-fluoro-8-methoxy-5,6,7,8- tetrahydroquinoline-5-carboxylate

IM II-s-1

¹H NMR (CDCl₃) delta 8.69 (1H, d, J=4.6 Hz), 7.79 (1H, d, J=7.9 Hz),7.31 (1H, dd, J=7.9, 4.6 Hz), 4.42 (1H, m), 3.79 (3 H, s), 3.57, (3 H,s), 2.55 (1H, m), 2.43-2.24 (3H, m).

MS (ESI) m/z: 240.2 (M+H)⁺.

IM II-s-2

¹H NMR (CDCl₃) delta 8.69 (1 H, br dd, J=4.6, 1.3 Hz), 7.68 (1H, dd,J=7.9, 1.3 Hz), 7.32 (1H, dd, J=7.9, 4.6 Hz), 4.41 (1H, m), 3.82 (3H,s), 3.54 (3H, s), 2.78 (1 H, m), 2.36-2.04 (3H, m).

MS (ESI) m/z: 240.1 (M+H)⁺.

IM II-s-3 ¹H NMR (CDCl₃) delta 8.69 (1 H, br dd, J=4.6, 1.3 Hz), 7.79(1H, dd, J=7.9, 1.3 Hz), 7.31 (1H, dd, J=7.9, 4.6 Hz), 4.42 (1H, m),3.79 (3 H, s), 3.57, (3 H, s), 2.55 (1 H, m), 2.43-2.24 (3H, m).

MS (ESI) m/z: 240.1 (M+H)⁺.

The following Examples were prepared by General Procedure A (Table 57).

TABLE 57 Ex- am- ples Structure Chemical Name Substrate Amine 333

(5R,8S)-N- (2,4-dichloro- 6-(hydroxymethyl) benzyl)-5-fluoro- 8-methoxy-5,6,7,8- tetrahydroquinoline- 5-carboxamide

334

(5S,8R)-N- (2,4-dichloro- 6-(hydroxymethyl) benzyl)-5-fluoro- 8-methoxy-5,6,7,8- tetrahydroquinoline- 5-carboxamide

335

(5S,8S)-N- (2,4-dichloro- 6-fluorobenzyl)- 5-fluoro- 8-methoxy-5,6,7,8-tetrahydroquinoline- 5-carboxamide

336

(5S,8S)-N-(2,3- dichlorobenzyl)- 5-fluoro-8- hydroxy-5,6,7,8-tetrahydroquinoline- 5-carboxamide

337

(5S,8S)-N- (2-chloro-4- fluorobenzyl)- 5-fluoro-8- methoxy-5,6,7,8-tetrahydroquinoline- 5-carboxamide

338

(5S,8S)-N- (2-chloro-4- (trifluoromethyl) benzyl)- 5-fluoro-8-methoxy-5,6,7,8- tetrahydroquinoline- 5-carboxamide

339

(5S,8S)-5-fluoro-8- methoxy-N-(2,3,4- trifluorobenzyl)- 5,6,7,8-tetrahydroquinoline- 5-carboxamide

340

(5S,8S)-N- (4-chloro-2- fluorobenzyl)- 5-fluoro-8- methoxy-5,6,7,8-tetrahydroquinoline- 5-carboxamide

341

(5S,8S)-5-fluoro-8- methoxy-N-(2,4,6- trifluorobenzyl)- 5,6,7,8-tetrahydroquinoline- 5-carboxamide

342

(5S,8S)-N-(2,4- difluorobenzyl)- 5-fluoro-8- methoxy-5,6,7,8-tetrahydroquinoline- 5-carboxamide

TABLE 58 LC MS Examples Method tR (min) [M + H]⁺ 333 A 1.45 413.1 334 A1.44 413.1 335 B 1.58 400.9 337 B 1.54 383.0 337 B 1.47 367.1 338 B 1.63417.0 339 C 1.46 368.9 340 C 1.52 366.9 341 C 1.42 368.9 342 C 1.41351.0

Ex 333

¹H NMR (CDCl₃) delta 8.66 (1H, br d, J=4.6 Hz), 7.57 (1H, br d, J=5.9Hz), 7.49 (1H, d, J=7.9 Hz), 7.44 (1H, d, J=2.0 Hz), 7.33 (1H, d, J=2.0Hz), 7.23 (1H, dd, J=7.9, 4.6 Hz), 4.73-4.67 (4H, m), 4.43 (1H, m), 3.90(1 H, br), 3.57 (3 H, s), 2.80-2.11 (4H, m).

Ex 334

¹H NMR was identified with the Example 333.

Intermediate (IM) II-s-4:

(5S,8S)-allyl8-(allyloxy)-5-fluoro-5,6,7,8-tetrahydroquinoline-5-carboxylate

A mixture of (5S,8S)-methyl5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxylate (100 mg,0.444 mmol, IM II-d-4) and 2 N aq. NaOH in MeOH (2.0 mL) was stirred atroom temperature for 1 h, the resulting solution was concentrated invacuo. The residue was added NMP (1.0 mL) and the mixture was addedsodium hydride (60% oil dispersant, 5 mg, 0.222 mmol) at 0° C. Themixture was warmed to room temperature and stirred for 20 min. Allylbromide (0.192 mL, 2.22 mmol) was added to the reaction mixture and themixture was heated at 60° C. for 6 h. The mixture was cooled to roomtemperature and stirred further 9 h. Water was added to the mixture andthe mixture was extracted with EtOAc. The extract was washed with brine,dried over Na₂SO₄, and concentrated in vacuo. The residue was purifiedby silica gel column chromatography (0- to 50% EtOAc/n-hexane, gradient)to afford 25 mg (19%) of the title compound.

¹H NMR (CDCl₃) delta 8.67 (1 H, br dd, J=4.6, 1.8 Hz), 7.68 (1 H, br dd,J=7.9, 1.8 Hz), 7.31 (1H, dd, J=7.9, 4.9 Hz), 5.95 (1 H, ddt, J=17.1,10.4, 5.5 Hz), 5.88 (1 H, ddt, J=17.1, 10.4, 5.5 Hz),5.32 (1H, ddt,J=17.1, 4.9, 1.8 Hz),5.30 (1H, ddt, J=17.1, 3.1, 1.2 Hz), 5.25 (1 H, brd J=10.4 Hz), 5.17 (1 H, ddt, J=10.4, 3.1, 1.2 Hz), 4.76-4.66 (2H, m),4.56 (1H, m), 4.30-4.21 (2H, m), 2.89 (1H, m), 2.33-2.15 (3H, m).

MS (ESI) m/z: 291.9 (M+H)⁺.

Intermediate (IM) I-s-1:

(5R,8R)-8-(allyloxy)-N-(2,4-dichlorobenzyl)-5-fluoro-5,6,7,8-tetrahydroquinoline-5-carboxamide

60% oil dispersant NaH (6 mg, 0.244 mmol) was added to a solution of(5R,8R)-methyl5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxylate (25 mg,0.111 mmol, IM II-d-6) in THF (1.0 mL) under N₂ atmosphere at 0° C.After being stirred at 0° C., allyl iodide (0.025 mL, 0.278 mmol) wasadded to the mixture and the mixture was stirred for 1 h. 60% oildispersant NaH (6 mg, 0.244 mmol) and allyl iodide (0.025 mL, 0.278mmol) was added to the mixture and the mixture was stirred further 1 h.Water was added to the mixture and acidified with 2 N hydrochloric acid.The mixture was concentrated in vacuo. The resulting residue was dilutedwith MeCN and toluene and the mixture was concentrated in vacuo. Thisprocedure was repeated 3 times to remove remaining water. The residuewas dissolved in 25% MeOH-THF (2.0 mL) and 2,4-dichlorobenzylamine (20mg, 0.111 mmol), triethylamine (0.025 mL, 0.179 mmol), and DMT-MM (40mg, 0.167 mmol) were added to the mixture. After being stirred at roomtemperature for 16 h, water was added to the mixture. The mixture wasextracted with EtOAc and washed with brine. The extract was dried overNa₂SO₄ and concentrated in vacuo to afford glass. The residual glass waspurified by preparative TLC (70% EtOAc/n-hexane) to afford 15 mg (33%)of the title compound as a white solid.

¹H NMR (CDCl₃) delta 8.64 (1 H, br dd, J=4.9, 1.8 Hz), 7.51 (1 H, br dd,J=7.9, 1.8 Hz), 7.44 (1H, d, J=1.8 Hz), 7.37 (1H, br d, J=7.9 Hz),7.27-7.22 (2H, m), 7.16 (1 H, br), 5.92 (1 H, ddt, J=17.1, 10.4, 5.5Hz), 5.29 (1 H, ddt, J=17.1, 3.7, 1.8 Hz), 5.14 (1 H, ddt, J=17.1, 3.7,1.8 Hz), 4.71-4.51 (3H, m), 4.27-4.17 (2H, m), 2.92 (1 H, m), 2.33-2.06(3H, m).

MS (ESI) m/z: 408.7 (M+H)⁺.

The following Intermediates were prepared from IM II-s-4 by GeneralProcedure A (Table 59).

TABLE 59 Intermediates Structure Chemical Name Amine I-s-2

(5S,8S)-8-(allyloxy)- N-(2-(((tert-butyldimethylsilyl)oxy)methyl)-4,6-dichlorobenzyl)- 5-fluoro-5,6,7,8- tetrahydroquinoline-5-carboxamide

I-s-3

(5S,8S)-8-(allyloxy)- N-(2-chloro-4- fluorobenzyl)-5- fluoro-5,6,7,8-tetrahydroquinoline- 5-carboxamide

I-s-4

(5S,8S)-8-(allyloxy)- 5-fluoro-N-(2,3,4- trifluorobenzyl)-5,6,7,8-tetrahydroquinoline- 5-carboxamide

I-s-5

(5S,8S)-8-(allyloxy)- N-(4-chloro-2- fluorobenzyl)-5- fluoro-5,6,7,8-tetrahydroquinoline- 5-carboxamide

I-s-6

(5S,8S)-8-(allyloxy)-N-(2,4- difluorobenzyl)-5-fluoro-5,6,7,8-tetrahydroquinoline- 5-carboxamide

I-s-7

(5S,8S)-8-(allyloxy)-N-(2,4- dichlorobenzyl)-5-fluoro-5,6,7,8-tetrahydroquinoline- 5-carboxamide

IM II-s-2

MS (ESI) m/z: 552.4 (M+H)⁺.

IM II-s-3

MS (ESI) m/z: 392.7 (M+H)⁺.

IM I-s-4

MS (ESI) m/z: 394.8 (M+H)⁺.

IM I-s-5

MS (ESI) m/z: 392.8 (M+H)⁺.

IM I-s-6

MS (ESI) m/z: 376.8 (M+H)⁺.

IM I-s-7

MS (ESI) m/z: 408.7 (M+H)⁺.

The following Examples were prepared by General Procedure C (Table 60).

In preparation of Example 343, the TBS group was deprotected on the SCXcartridge column.

TABLE 60 Examples Structure Chemical Name Substrate 343

(5S,8S)-N-(2,4-dichloro- 6- (hydroxymethyl)benzyl)- 5-fluoro-8-(2-hydroxyethoxy)-5,6,7,8- tetrahydroquinoline-5- carboxamide

344

(5S,8S)-N-(2-chloro-4- fluorobenzyl)-5-fluoro-8- (2-hydroxyethoxy)-5,6,7,8- tetrahydroquinoline-5- carboxamide

345

(5S,8S)-5-fluoro-8-(2- hydroxyethoxy)-N- (2.3.4-trifluorobenzyl)-5,6,7,8- tetrahydroquinoline-5- carboxamide

346

(5S,8S)-N-(4-chloro-2- fluorobenzyl)-5-fluoro-8- (2-hydroxyethoxy)-5,6,7,8- tetrahydroquinoline-5- carboxamide

347

(5S,8S)-N-(2,4- difluorobenzyl)-5-fluoro- 8-(2-hydroxyethoxy)- 5,6,7,8-tetrahydroquinoline-5- carboxamide

348

(5R,8R)-N-(2,4- dtchlorobenzyl)-5- fluoro-8-(2- hydroxyethoxy)-5.6,7,8-tetrahydroquinoline-5- carboxamide

TABLE 61 LC MS Examples Method tR (min) [M + H]⁺ 343 C 1.37 442.9 344 C1.39 397.0 345 C 1.36 399.0 346 C 1.41 397.1 347 C 1.31 381.0 348 C 1.49413.0

Example 349(5S,8S)-N-(2,4-dichlorobenzyl)-8-(2,3-dihydroxypropoxy)-5-fluoro-5,6,7,8-tetrahydroquinoline-5-carboxamide

A mixture of AD-Mix beta (250 mg) in 50% tert-BuOH-water (3.0 mL) wasstirred at room temperature until the two clear phases formed. Aftercooling to 0° C., a solution of(5S,8S)-8-(allyloxy)-N-(2,4-dichlorobenzyl)-5-fluoro-5,6,7,8-tetrahydroquinoline-5-carboxamide(24 mg, 0.059 mmol, IM I-s-7) in THF (1.0 mL) was added to the mixture.The resulting mixture was stirred at 0° C. overnight. The mixture wasfiltered through a pad of celite, the filter cake was washed with THF.The filtrate was evaporated in vacuo to remove the volatile. The residuewas diluted with brine and extracted with EtOAc twice. The extracts werecombined and dried over Na₂SO₄. After removal of the solvent, theresidue was purified by silica gel column chromatography (50%EtOAc/n-hexane then 5% MeOH/EtOAc) to afford 24 mg (92%) of the titlecompound.

¹H NMR (CDCl₃) delta 8.61 (1H, m), 7.55 (1H, m), 7.50 (1H, d, J=1.8 Hz),7.36 (1H, br d, J=7.9 Hz), 7.31-7.23 (2H, m), 7.20 (1H, br d, J=5.5 Hz),4.67-4.56 (3H, m), 3.92-3.52 (5H, m), 2.82 (1H, m), 2.7 (1 H, br),2.36-2.07 (3H, m), 1.8 (1 H, br).

LCMS (ESI) m/z: 443.2 (M+H)⁺, tR 1.45 min (Method D).

Intermediate (IM) I-p-1:

Procedure: Scheme 13, Step 1

S-((5S)-5-((2,4-dichlorobenzyl)carbamoyl)-5-fluoro-5,6,7,8-tetrahydroquinolin-8-yl)benzothioate

Bis(2-methoxyethyl) azodicarboxylate (57 mg, 0.244 mmol) was added to asolution of triphenylphosphine (64 mg, 0.244 mmol) in THF (2.0 mL) at 0°C. under N₂ atmosphere. The reaction mixture was stirred at 0° C. for 30min, and then a solution of

(5S,8S)-N-(2,4-dichlorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide (60 mg, 0.163 mmol, Ex 133) and thiobenzoic acid (34 mg, 0.244mmol) in THF (1.0 mL) was added dropwise to the mixture. After beingstirred at 0° C. for 20 h, water was added to the mixture and themixture was extracted with EtOAc. The extract was washed with brine,dried over Na₂SO₄, and concentrated. The residue was purified by columnchromatography (20- to 35% EtOAc/n-hexane, gradient) to afford 25 mg(31%) of the title compound.

¹H NMR (CDCl₃) delta 8.66-8.63 (1H, m), 8.01-7.96 (2H, m), 7.60-7.17(9H, m), 5.30 (0.4 H, br), 5.24 (0.6 H, m), 4.75-4.56 (2H, m), 2.87-2.14(4H, m).

MS (ESI) m/z: 488.6 (M+H)⁺.

Intermediate (IM) I-q-1:

Procedure: Scheme 13, Step 2

(5S)-N-(2,4-dichlorobenzyl)-5-fluoro-8-(methylthio)-5,6,7,8-tetrahydroquinoline-5-carboxamide

A solution ofS-((5S)-5-((2,4-dichlorobenzyl)carbamoyl)-5-fluoro-5,6,7,8-tetrahydroquinolin-8-yl)benzothioate(25 mg, 0.051 mmol, IM I-p-1) in methanol (1.0 mL) was added 1 N aq.NaOH (0.06 mL, 0.06 mmol) and dimethyl sulfate (8 mg, 0.06 mmol) at roomtemperature. The mixture was stirred at room temperature for 2 h andconcentrated in vacuo. Water was added to the resulting residue andextracted with EtOAc. The extract was washed with brine, dried overNa₂SO₄ and concentrated in vacuo. The residue was purified by SCX columnto afford 18 mg (88%) of the title compound as a glass.

¹H NMR (CDCl₃) delta 8.67-8.58 (1H, m), 7.57-7.14 (6H, m), 4.68-4.53(2H, m), 4.18-4.14 (1H, m), 3.49 (3 H, s), 3.03-2.86 (0.4 H, m),2.72-2.64 (0.6 H, m), 2.59-2.10 (3H, m).

MS (ESI) m/z: 400.5 (M+H)⁺.

Intermediate (IM) I-q-2:

Procedure: Scheme 13, Step 2

(5S)-N-(2,4-dichlorobenzyl)-5-fluoro-8-((2-hydroxyethyl)thio)-5,6,7,8-tetrahydroquinoline-5-carboxamide

A solution ofS-((5S)-5-((2,4-dichlorobenzyl)carbamoyl)-5-fluoro-5,6,7,8-tetrahydroquinolin-8-yl)benzothioate (24 mg, 0.049 mmol, IM I-p-1) in methanol (1.0 mL) wasadded 1 N aq. NaOH (0.06 mL, 0.06 mmol) and(2-bromoethoxy)(tert-butyl)dimethylsilane (18 mg, 0.074 mmol) at roomtemperature. The mixture was stirred at room temperature for 2 h andconcentrated in vacuo. Water was added to the residue and the mixturewas extracted with EtOAc. The extract was washed with brine, dried overNa₂SO₄, and concentrated in vacuo. The resulting residue was purified bySCX column to afford 16 mg (76%) of the title compound as a glass.

¹H NMR (CDCl₃) delta 8.57 (0.5 H, dd, J=4.9, 1.8 Hz), 8.56 (0.5 H, dd,J=4.9, 1.8 Hz), 7.53 (0.5 H, d, J=7.9 Hz), 7.49 (0.5 H, d, J=7.9 Hz),7.45 (1H, d, J=1.8 Hz), 7.39 (0.5 H, d, J=7.9 Hz), 7.34 (0.5 H, d, J=7.9Hz), 7.31-7.14 (3H, m), 4.68-4.53 (2 H, m), 4.47 (0.5 H, br), 4.29 (0.5H, br), 3.95-3.86 (2H, m), 3.48 (1 H, br), 3.05-2.68 (3H, m), 2.53-2.12(3H, m).

MS (ESI) m/z: 428.6 (M+H)⁺.

General Procedure: Scheme 13, Step 3

The following Examples were prepared by General Procedure X (Table 62).

TABLE 62 Examples Structure Chemical Name Substrate 350

(5S)-N-(2,4- dichlorobenzyl)-5- fluoro-8- (methylsulfanyl)- 5,6,7,8-tetrahydroquinoline-5- carboxamide

351

(5S)-N-(2,4- clichlorebenzyl)-5- fluoro-8-((2- hydroxyethyl)sulfenyl)-5,6,7,8- letrahydroquineline-5- carboxamide

Ex 350

¹H NMR (CDCl₃) delta 8.66-8.60 (1H, m), 7.68 (1H, dd, J=7.9, 1.8 Hz),7.45 (0.5 H, d, J=1.8 Hz), 7.39 (0.5 H, d, J=1.8 Hz), 7.37-7.21 (3H, m),7.15 (0.5 H, br), 7.00 (0.5 H, br), 4.62-4.50 (2H, m), 4.44 (1H, m),3.30 (1.5 H, s), 3.16 (1.5 H, s), 3.03-2.62 (3H, m), 2.42-2.27 (1H, m).

LCMS (ESI) m/z: 430.5 (M+H)⁺, tR 1.58 min (Method C).

Ex 351

¹H NMR (CDCl₃) delta 8.59 (1H, dd, J=4.9, 1.2 Hz), 7.72 (1H, dd, J=7.9,1.2 Hz), 7.45 (1H, d, J=2.4 Hz), 7.41-7.22 (3H, m), 7.14 (1 H, br), 4.80(1H, m), 4.70 (1 H, br), 4.62-4.49 (2H, m), 4.24-4.17 (2H, m), 3.95-3.89(1H, m), 3.42-3.36 (1H, m), 3.07-2.66 (3H, m), 2.43-2.30 (1H, m).

LCMS (ESI) m/z: 460.8 (M+H)⁺, tR 1.50 min (Method C).

The following Intermediate was prepared by General Procedure AB (Table63).

General Procedure AB

Deoxo-Fluor(Trademark) (2.0 eq.) was added to a solution of substrate(1.0 eq.) in CH₂Cl₂ (0.15 M) and stirred for 1 h. The mixture was pouredinto water and extracted with EtOAc. The extract was dried over Na₂SO₄and concentrated in vacuo. The resulting residue was purified by silicagel column chromatography.

TABLE 63 Intermediate Structure Chemcal Name Substrate II-y-1

(5R,8S)-methyl 5,8-difluoro-5.6,7,8- tetrahydroquinoline-5-carboxylate

IM II-y-1

¹H NMR (CDCl₃) delta 8.74 (1 H, d, J 4.6 Hz), 7.87 (1 H, d, J 7.9 Hz),7.39 (1H, in), 5.61 (1H, br d, J=49.4 Hz), 3.80 (3H, s), 2.57-2.40 (4H,m).

MS (ESI) m/z: 228.1 (M+H).

The following Examples were prepared by General Procedure A (Table 64).

TABLE 64 Examples Structure Chemical Name Substrate Amino 352

(5R,8S)-N-(2-chloro-3- (trifluoromethyl)benzyl)- 5,8-difluoro-5,6,7,8-tetrahydroquinoline-5- carboxamide

353

(5R,8S)-N-(2,4- dichlorobenzyl)-5,8- difluoro-5,6,7,8-tetrahydroquinoline-5- carboxamide

354

(5R,8S)-N-(2,3- dichlorobenzyl)-5.8- difluoro-5,6,7,8-tetrahydroquinaline-5- carboxamide

TABLE 65 LC MS Examples Method tR (min) [M + H]⁺ 352 A 1.64 405.1 353 A1.64 371.1 354 A 1.61 371.1

Procedure: Scheme 16, Step 1

Intermediate (IM)XVIII-1, 1-(2-chloropyridin-3-yl)pent-4-en-1-one

To a solution of 3-bromo-2-chloro pyridine (4.0 g, 20.8 mmol) in THF(100 mL) was added dropwise 1.3 M 2-propyl magnesium chloride lithiumchloride complex in THF solution (18.5 ml, 25.0 mmol) at −10° C. underAr atmosphere. The reaction mixture was stirred at the same temperaturefor 15 min. Then a THF solution of pent-4-enoyl chloride (3.2 g, 27.0mmol) was added to the mixture at −40° C. After addition, the mixturewas stirred at the same temperature for 1.5 h. The mixture was pouredinto aq. NH₄Cl at 0° C. The mixture was extracted with EtOAc twice andwashed with aq. NaHCO₃ and brine. The combined extracts were dried overNa₂SO₄ and concentrated in vacuo. The insoluble material of theresulting residue was removed by filtration and washed with EtOAc. Anactivated charcoal was added to the filtrate. The mixture was stirred at45° C. for 1.0 h and filtered through a pad of celite. The filtrate wasdistilled at reduced pressure to afford 2.9 g (72%) of the titlecompound.

¹H NMR (CDCl₃) delta 8.49 (1H, dd, J=4.9, 2.0 Hz), 7.81 (1H, dd, J=7.6,2.0 Hz), 7.34 (1H, dd, J=7.6, 4.8 Hz), 5.77-5.91 (1H, m), 4.99-5.13 (3H,m), 3.11 (2 H, t, J=7.3 Hz, 2H), 2.43-2.54 (2H, m).

MS (ESI) m/z: 196.3 (M+H)⁺.

Procedure: Scheme 16, Step 2

Intermediate (IM) XIX-1, 8-methylene-7,8-dihydroquinolin-5(6H)-one

A mixture of 1-(2-chloropyridin-3-yl)pent-4-en-1-one (300 mg, 1.53 mmol,IM XVIII-1), triethylamine (0.64 mL, 4.61 mmol), Xantphos (17.7 mg,0.031 mmol), and Pd(OAc)₂ (6.9 mg, 0.031 mmol) in MeCN (1.53 mL) washeated at reflux. After being refluxed for 15 h, the mixture was cooledto room temperature. The mixture was filtered with celite and thefiltrate was concentrated in vacuo. To the residue was addedEtOAc/n-hexane and the mixture was stirred for 15 min at roomtemperature. The mixture was filtered with celite and the filtrate waswashed with water, dried over Na₂SO₄. The residue was distilled atreduced pressure to afford 238 mg (97%) of the title compound.

¹H NMR (CDCl₃) delta 8.76 (1H, dd, J=4.6, 1.8 Hz), 8.28 (1H, dd, J=8.0,1.8 Hz),7.34 (2H, dd, J=8.0, 4.7 Hz), 6.38 (1H, s), 5.47 (1H, d, J=1.3Hz), 2.89-2.98 (2H, m), 2.75-2.85 (2H, m).

MS (ESI) m/z: 160.3 (M+H).

Procedure: Scheme 16, Step 3

Intermediate (IM) XX-1,

5-fluoro-8-methylene-5,6,7,8-tetrahydroquinoline-5-carbonitrile

To a solution of 8-methylene-7,8-dihydroquinolin-5(6H)-one (300 mg, 1.9mmol, IM XIX-1) in dichloromethane (15 mL) was added trimethylsilylcyanide (243 microL, 2.45 mmol) and NMO (132 mg, 1.13 mmol) at 25° C.under Ar atmosphere. The reaction mixture was stirred at the sametemperature for 4 h. Then Deoxo-Fluor™ (382 microL 2.07 mmol) was addedto the mixture at 0° C. The mixture was stirred at the same temperaturefor 2 h and the mixture was poured into aq. NaHCO₃ at 0° C. The mixturewas extracted with dichloromethane. The organic layer was dried overNa₂SO₄ and removed solvent in vacuo. The resulting residue was purifiedby silica gel column chromatography (30% EtOAc/n-hexane) to afford 256mg (72%) of the title compound.

¹H NMR (CDCl₃) delta 8.70 (1 H, dt, J=4.6, 1.6 Hz), 8.02 (1 H, dt,J=8.0, 1.4 Hz), 7.35 (1H, dd, J=8.0, 4.7 Hz), 6.45 (1H, s), 5.37 (1H,s), 2.77-2.97 (3H, m), 2.42-2.62 (2H, m).

MS (ESI) m/z: 189.4 (M+H).

Procedure: Scheme 16, Step 4

Intermediate (IM) II-e-2-1, methyl

5-fluoro-8-methylene-5,6,7,8-tetrahydroquinoline-5-carboxylate

The title compound was prepared according to the procedure as describedin General Procedure: Scheme 2, Step 3 using5-fluoro-8-methylene-5,6,7,8-tetrahydroquinoline-5-carbonitrile (IMXX-1).

Procedure: Scheme 17, Step 1

Intermediate (IM) XXII-1, methyl2-(2-chloropyridin-3-yl)-2-hydroxyhex-5-enoate

To a solution of 3-bromo-2-chloropyridine (1.79 g, 9.30 mmol) in THF (10mL) was added dropwise 1.3 M 2-propylmagnesium chloride lithium chloridecomplex in THF (7.2 mL, 9.4 mmol) at −15° C. and the mixture was stirredat the same temperature for 1 h. A solution of methyl 2-oxohex-5-enoate(1.33 g, 9.36 mmol) in THF (3 mL) was added to the mixture at −40° C.The mixture was stirred at the same temperature for 2 h. Then thereaction was quenched with sat. aq. NH₄Cl. The mixture was extractedwith EtOAc twice. The combined organic layer was washed with brine,dried over Na₂SO₄, and removed solvent in vacuo. The residue waspurified by silica gel column chromatography (25% EtOAc/n-hexane) toafford 1.78 g (74%) of the title compound.

¹H NMR (CDCl₃) delta 8.35 (1H, dd, J=4.7, 1.8 Hz), 7.97 (1H, dd, J=7.8,1.8 Hz), 7.26-7.33 (1H, m), 5.83 (1 H, ddt, J=17.0, 10.4, 6.4, 6.4 Hz),4.98-5.10 (2H, m), 3.84 (1H, s), 3.78 (3H, s), 2.14-2.40 (3H, m),1.96-2.07 (1H, m).

Procedure: Scheme 17, Step 2

Intermediate (IM) II-e-2-5, methyl

5-hydroxy-8-methylene-5,6,7,8-tetrahydroquinoline-5-carboxylate

The title compound was prepared according to the procedure as describedin General Procedure: Scheme 16, Step 2 using methyl2-(2-chloropyridin-3-yl)-2-hydroxyhex-5-enoate (IM XXII-1).

Procedure: Scheme 18, Step 1

Intermediate (IM) XXIII-1,

5-fluoro-8-methylene-5,6,7,8-tetrahydroquinoline-5-carboxylic acid

A mixture of methyl5-fluoro-8-methylene-5,6,7,8-tetrahydroquinoline-5-carboxylate (3.0 g,13.6 mmol, IM II-e-2-1) and 2 N aq. NaOH (14 mL, 28.0 mmol) in MeOH (67mL) was stirred at room temperature for 1.5 h, and then the mixture wasconcentrated in vacuo. 10% aq. citric acid (90 mL) was added to themixture. The mixture was extracted with EtOAc. The organic layer wasdried over Na₂SO₄ and concentrated in vacuo to afford 1.57 g (56%) ofthe title compound.

¹H NMR (CDCl₃) delta 8.73 (1H, d, J=4.9 Hz), 8.28 (2 H, br s), 7.95 (1H,d, J=7.6 Hz), 7.35 (1H, dd, J=7.9, 5.0 Hz), 6.24 (1H, s), 5.39 (1H, s),2.75-2.91 (2H, m), 2.44-2.65 (1H, m), 2.26-2.40 (1H, m).

MS (ESI) m/z: 208.1 (M+H)⁺.

Procedure: Scheme 18, Step 2

Intermediate (IM) XXIV,

5-fluoro-8-(iodomethyl)-5,6,7,8-tetrahydro-8,5-(epoxymethano)quinolin-10-one

To a solution of5-fluoro-8-methylene-5,6,7,8-tetrahydroquinoline-5-carboxylic acid (2.0g, 9.65 mmol, IM XXIII-1) in MeCN (100 mL) was added NaHCO₃ (1.7 g, 19.6mmol) and iodine (5.0 g, 19.6 mmol) at room temperature. The reactionmixture was stirred at the same temperature for 3 h. Then sat. aq.Na₂S₂O₃ was added to the mixture. The mixture was extracted with EtOAcand washed with brine. The extract was dried over Na₂SO₄ andconcentrated in vacuo. The residue was purified by silica gel columnchromatography (30% EtOAc/n-hexane) to afford 2.6 g (81%) of the titlecompound.

¹H NMR (CDCl₃) delta 8.59 (1H, dd, J=5.1, 1.5 Hz), 7.88 (1H, dd, J=7.6,1.5 Hz), 7.43 (1H, dd, J=7.7, 5.0 Hz), 4.03-4.12 (2H, m), 2.71-2.81 (1H,m), 2.51 (1 H, tdd, J=11.3, 11.3, 5.5, 3.4 Hz), 2.09 (1 H, tdd, J=11.7,11.7, 4.6, 3.2 Hz), 1.91-2.00 (1H, m).

MS (ESI) m/z: 333.9 (M+H)⁺.

Pharmacological Assays

The ability of the 5,6,7,8-tetrahydroquinoline and6,7-dihydro-5H-cyclopenta[b]pyridine derivatives of the formula (I) toinhibit the P2X7 channel was measured by Ca²⁺ influx assay andelectrophysiology assay described below.

human P2X7 Functional Assay

The functional activity of compounds was determined by measuring changesin intracellular calcium concentration using a Ca²⁺-sensitivefluorescent dye, Fluo-4 (Molecular Probes). The changes in fluorescentsignal were monitored by the cell imaging technology by HamamatsuPhotonics's Functional Drug Screening System (FDSS). Increases inintracellular Ca²⁺ concentration were readily detected upon activationwith BzATP.

Cell Maintenance:

HEK293 cells stably expressing human P2X7 (GenBank accession numberBC011913) carrying a C-terminal FLAG tag were grown in T225 flasks, in a5% CO2 humidified incubator to about 80% confluence. Media compositionconsisted of Dulbecco's Modified Eagle Medium (high glucose), 10% fetalbovine serum (BSA), 100 units/microM Penicillin, 100 microg/mLStreptomycin and 250 microg/mL Geneticine.

Protocol:

Day One:

1. Plate-out HEK293-human P2X7 cells (40 microL medium containing 10,000cells per well) into poly-D-lysine coated 384-well plates (Corning) at24 h prior to assay.

2. Incubate at 37° C. in 5% CO₂.

Day Two:

1. Wash each well with 80 microL of assay buffer (20 mM HEPES, 1×HBSS,pH 7.4 adjusted with NaOH) three times and leave 20 microL using platewasher, ELx-405 Select CW (BIO-TEK).

2. Add 20 microL of assay buffer containing 2.5 mM probenecid, 0.5microM Fluo-4-AM (Molecular Probes) and 0.1% Pluronic F-127 to eachwell.

3. Incubate the plate at 37° C. in 5% CO₂ for 1 h.

4. Wash each well with 80 microL of assay buffer (see below) three timesand leave 20 microL using plate washer, ELx-405 Select CW (BIO-TEK).

5. Test compounds were prepared at 100× the test concentration in DMSOby serial dilution with Biomek-FX liquid handling instrument. 33×diluted compound solutions in assay buffer were prepared in intermediatecompound plate with Biomek-NX liquid handling instrument. A further 3×dilution occurred in below steps 6 and 7.

6. Add 20 microL of 33× diluted compound solutions into each well andleave the plate for 10 min under the dark at room temperature.

7. Measure activity by FDSS as follows:

-   -   Set the assay plate on the stacker of FDSS.    -   Start the detection of fluorescence intensity at 540 nm by 480        nm exicitation.    -   After 30 seconds, add 20 microL of assay buffer containing 240        microM BzATP (final concentration 80 microM).

IC₅₀ values for compounds of the present invention were determined from7-point dose-response studies. Curves were generated using the averageof duplicate wells for each data point. Finally, the IC₅₀ values arecalculated with the best-fit dose curve determined by XLfit (ID BusinessSolutions Ltd.).

Antagonistic activities with respect to the human P2X7 receptor (IC₅₀values) of exemplified compounds are displayed in Table 66.

TABLE 66 A: <50 nM, B: 50- to 100 nM, C: 101 - to 300 nM, D: 301- to1,000 nM, E: 1,001 - to 3,000 nM Examples IC₅₀ 1 A 2 A 3 D 4 A 5 E 6 A 7A 8 A 9 A 10 A 11 A 12 A 13 A 14 A 15 D 16 A 17 B 18 A 19 A 20 A 21 A 22A 23 A 24 A 25 C 26 A 27 A 28 B 29 A 30 A 31 B 32 A 33 A 34 A 35 A 36 A37 A 38 C 39 A 40 A 41 A 42 A 43 A 44 A 45 A 46 A 47 A 48 A 49 A 50 A 51A 52 A 53 A 54 A 55 A 56 A 57 A 58 A 59 A 60 C 61 A 62 C 63 C 64 A 65 D66 A 67 C 68 A 69 D 70 A 71 D 72 A 73 C 74 C 75 E 76 B 77 D 78 A 79 D 80B 81 A 82 A 83 C 84 A 85 A 86 C 87 B 88 A 89 C 90 C 91 C 92 C 93 E 94 E95 E 96 E 97 A 98 C 99 A 100 A 101 C 102 A 103 C 104 A 105 D 106 A 107 C108 D 109 D 110 D 111 D 112 C 113 A 114 C 115 A 116 D 117 A 118 A 119 A120 E 121 B 122 B 123 C 124 C 125 C 126 A 127 A 128 A 129 A 130 A 131 A132 A 133 A 134 C 135 A 136 C 137 A 138 C 139 A 140 D 141 A 142 A 143 D144 A 145 C 146 A 147 A 148 A 149 A 150 A 151 A 152 A 153 A 154 A 155 B156 C 157 A 158 A 159 A 160 C 161 A 162 C 163 A 164 C 165 A 166 C 167 A168 C 169 A 170 A 171 A 172 C 173 B 174 A 175 A 176 A 177 A 178 A 179 A180 A 181 A 182 A 183 A 184 A 185 A 186 A 187 A 188 A 189 A 190 A 191 A192 A 193 A 194 A 195 A 196 A 197 A 198 A 199 B 200 B 201 B 202 B 203 B204 B 205 B 206 C 207 C 208 C 209 C 210 C 211 C 212 C 213 C 214 C 215 C216 C 217 C 218 D 219 D 220 D 221 D 222 D 223 D 224 D 225 D 226 E 227 E228 E 229 A 230 A 231 A 232 A 233 C 234 D 235 E 236 E 237 A 238 A 239 C240 D 241 A 242 A 243 D 244 E 245 A 246 A 247 A 248 A 249 B 250 C 251 A252 A 253 A 254 D 255 C 256 A 257 C 258 A 259 A 260 D 261 A 262 A 263 A264 A 265 A 266 A 267 A 268 A 269 A 270 A 271 D 272 A 273 A 274 A 275 E276 D 277 A 278 E 279 A 280 A 281 D 282 A 283 A 284 A 285 A 286 A 287 A288 A 289 A 290 A 291 C 292 B 293 E 294 B 295 A 296 B 297 D 298 A 299 C300 A 301 B 302 C 303 E 304 A 305 A 306 A 307 D 308 C 309 E 310 A 311 B312 A 313 B 314 C 315 E 316 A 317 A 318 D 319 A 320 A 321 A 322 C 323 C324 B 325 E 326 A 327 A 328 C 329 B 330 D 331 B 332 E 333 C 334 A 335 A336 A 337 A 338 A 339 A 340 A 341 B 342 B 343 A 344 A 345 A 346 A 347 B348 C 349 A 350 A 351 A 352 A 353 B 354 B

rat P2X7 Functional Assay

The functional activity of compounds was determined by measuring changesin intracellular calcium concentration using a Ca²⁺-sensitivefluorescent dye, Fluo-4 (Molecular Probes). The changes in fluorescentsignal were monitored by the cell imaging technology by HamamatsuPhotonics's Functional Drug Screening System (FDSS). Increases inintracellular Ca²⁺ concentration were readily detected upon activationwith BzATP.

Cell Maintenance:

HEK293 cells stably expressing rat P2X7 (GenBank accession numberNM_019256) were grown in Corning CellBIND cell culture flasks, in a 5%CO₂ humidified incubator to about 80% confluence. Media compositionconsisted of Dulbecco's Modified Eagle Medium (high glucose), 10% fetalbovine serum (BSA), 100 units/microL Penicillin, 100 microg/mLStreptomycin and 250 microg/mL Geneticine.

Protocol:

Day One:

1. Plate-out HEK293-human P2X7 cells (40 microL medium containing 10,000cells per well) into poly-D-lysine coated 384-well plates (Corning) at24 h prior to assay. Plate-out HEK293-rat P2X7 cells (40 microL mediumcontaining 5,000 cells per well) into poly-D-lysine coated 384-wellplates (BD Falcon) at 24 h prior to assay.

2. Incubate at 37° C. in 5% CO₂.

Day Two:

1. Wash each well with 80 microL of assay buffer (20 mM HEPES, 1×HBSS,pH 7.4 adjusted with NaOH) three times and leave 20 microL using platewasher, ELx-405 Select CW (BIO-TEK).

2. Add 20 microL of assay buffer containing 2.5 mM probenecid, 0.5microM Fluo-4-AM (Molecular Probes) and 0.1% Pluronic F-127 to eachwell.

3. Incubate the plate at 37° C. in 5% CO₂ for 1 h.

4. Wash each well with 80 microL of assay buffer (see below) three timesand leave 20 microL using plate washer, ELx-405 Select CW (BIO-TEK).

5. Test compounds were prepared at 100× the test concentration in DMSOby serial dilution with Biomek-FX liquid handling instrument. 33×diluted compound solutions in assay buffer were prepared in intermediatecompound plate with Biomek-NX liquid handling instrument. A further 3×dilution occurred in below steps 6 and 7.

6. Add 20 microL of 33× diluted compound solutions into each well andleave the plate for 10 min under the dark at room temperature.

7. Measure activity by FDSS as follows:

-   -   Set the assay plate on the stacker of FDSS.    -   Start the detection of fluorescence intensity at 540 nm by 480        nm exicitation.    -   After 30 seconds, add 20 microL of assay buffer containing 30        microM BzATP (final 10 microM).

IC₅₀ values for compounds of the present invention were determined from7-point dose-response studies. Curves were generated using the averageof duplicate wells for each data point. Finally, the IC₅₀ values arecalculated with the best-fit dose curve determined by XLfit (ID BusinessSolutions Ltd.).

Antagonistic activities with respect to the rat P2X7 receptor (IC₅₀<1uM) of exemplified compounds are displayed in Table 67.

TABLE 67 Examples 1 2 3 6 7 8 9 10 11 12 13 14 16 18 19 20 21 22 23 2425 26 27 28 29 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 5051 52 53 54 55 56 57 58 59 60 61 62 64 66 67 68 70 72 74 76 78 80 81 8283 84 85 87 88 89 97 100 102 104 106 107 108 110 111 115 117 118 121 122126 127 128 129 130 131 132 133 134 135 136 137 139 141 142 144 146 148149 150 152 153 154 157 158 159 161 163 165 167 168 169 170 171 172 174175 176 177 178 179 180 182 183 184 185 187 189 190 192 193 195 196 199201 203 205 206 208 221 229 230 231 232 233 234 237 238 239 240 241 242245 246 247 248 249 250 251 252 253 254 256 257 258 259 260 261 262 263264 265 266 267 268 269 270 272 273 274 277 279 280 281 282 283 284 285286 287 288 289 290 291 292 294 295 296 297 298 299 300 301 302 303 304305 306 307 308 309 310 311 312 313 314 315 316 317 318 319 320 321 322323 324 326 327 328 329 333 334 335 336 337 338 339 340 341 342 343 344345 346 347 349 350 351 352

All tested compounds of the invention show higher IC₅₀ values in humandofetilide binding than IC₅₀ values in P2X7 functional assay describedabove.

Metabolic Stability Assay:

Human Liver Microsomal Clearance of Test Compounds.

The in vitro elimination half-life estimates (t_(1/2)) and in vitrointrinsic clearance values (hCL_(int,u)) were observed from metabolicstability in human liver microsomes.

Incubation with Liver Microsomes Stock solutions of test compound wereprepared at 10 mM (as active compound) in DMSO. The stock solution wasdiluted immediately before use to 50 microM using 50% acetonitrile-watermixture solution (v/v) to produce working solution. TheNADPH-regenerating solution was prepared on the day of analysis bydiluting 1 volume of 80 mM NADP⁺ (ORIENTAL YEAST) with 1 volume of 240mM MgCl₂ (WAKO) and 1 volume of 320 mM of glucose-6-phosphate(Sigma-Aldrich) and 1 volume of 32 U/mL of glucose-6-phosphatedehydrogenase (Sigma-Aldrich) and 2 volume of 200 mM UDP-GA (Nacalai)and 2 volume of 6.6 mM beta-NAD (ORIENTAL YEAST), respectively.Immediately prior to use, the reaction mixture was produced mixing 1volume of the NADPH-regenerating solution with 6.8 volume of 125 mMpotassium phosphate assay buffer. Human liver microsomes (XenoTech,pooled, mixed-gender human microsomes) were diluted to 2.5 mg protein/mLusing 125 mM potassium phosphate assay buffer. Two microliters ofworking solution of each test compound and 78 microL of reaction mixturewere added to 96 well cluster tubes (Micronic) in duplicate.

The tubes were placed in an incubator at 37° C. for 5 minutes beforeadding the human liver microsomes. A 20 microL of aliquot of the humanliver microsome solution (2.5 mg protein/mL) was added to each originalwell to initiate metabolism. Incubation was performed at 37° C. At 15minutes, the plate was removed from the incubator and a solutioncontaining internal standard (200 microL, 1 microM reserpine, 50 nMbuspirone and 1 microM tolbutamide in 100% acetonitrile) was added toeach well. The plate was then spun in a centrifuge at 3500 rpm for 15minutes at 4° C. A supernatant was transferred from each well to a96-well shallow plate and then diluted with 4 volume of the mobile phase(A).

LC-MS/MS Analysis

Quantitative analysis of test compound in quenched reaction mixture wasperformed using the LC-MS/MS system, which consisted of an Agilent 1100series gradient HPLC pump (Agilent Technologies), a CTC HTS PALAutosampler (AMR), and a Sciex API 3200 triple quadrupole massspectrometer (Sciex) equipped with a turbo ionspray interface. TheChromatographic separation was achieved using reverse phase HPLC with anInert Sustain RP C18 50×2.1 mm column (GL Science) or Capcell Pak RP C1850×2.1 mm column (Shiseido). The column temperature was 40° C., and theflow rate was 0.4 mL/min. The mobile phase consisted of 2 solvents: (A)0.1% formic acid in water and (B) acetonitrile or 0.1% formic acid inacetonitrile. The compounds were eluted with a step gradient achieving5% to 90% of B in 0.7 min, 90% of B in 1.3 min and then returned toinitial conditions for equilibration (1.5 or 1.6 min). The massspectrometer was operated in multiple-reaction-monitoring mode.Integration of test compound and internal standard peak was performedusing Analyst Software (version 1.6). The area ratio of each testcompound was calculated by comparing the peak area of the compound tothe peak area of an internal standard.

Calculation of Human Liver Microsomal Intrinsic Clearance (hCL_(int,u))

The mean peak area ratios were calculated by averaging the peak arearatios (n=2) of a compound and internal standard for each sample.Metabolic stability was determined by plotting the natural logarithm ofthe mean peak area ratio of unchanged test compound as a function oftime. Percent remaining was calculated by determining the ratio of themean peak area ratio at incubation time to the mean peak area ratio ofthe time-zero samples. The rate of loss of test compound was calculatedusing the equation k=[Ln(C₀)−Ln(C)]/incubation time, where C₀ was theinitial mean peak area ratio of the test compound, C was the mean peakarea ratio of test compound remaining after incubation (C=C₀×remainingratio), and the incubation time was 15 min. The t_(1/2) was estimatedusing the equation t_(1/2)=0.693/k. The hCL_(int,u) was estimated usingthe equation hCL_(int,u)=k/(microsomal proteinconcentration)×(microsomal protein per gram of liver)×(liver mass perkilogram of body mass)/(human microsomal fu), where the microsomalprotein concentration was 0.5 mg/mL, and the physical and physiologicalscaling factors were used such as the microsomal protein per gram ofliver (48.8 mg) and, the liver mass per kilogram of body mass (25.7 g),and the human microsomal fu was determined experimentally from the humanliver microsomal binding assay.

The compounds of this invention show preferable stability, which showthe above-mentioned practical use.

Drug-Drug Interaction Assay

Cytochrome P450 Inhibition of Test Compounds.

Incubation with recombinant CYP and chemiluminescent probes

CYP inhibition assays (CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6 and 3A4) wereperformed with recombinant CYP enzyme (BD Gentest) and Promega assaykits (P450-Glo Assays) in 384 well plate (Corning). Each product'scatalog number is shown in Table 68.

Stock solutions of test compound were prepared at 10 mM (as activecompound) in DMSO. NADPH-regenerating solution for each well wasprepared on the day of analysis by diluting 0.4 microL of NADPH-Areagent (BD Gentest), 0.08 microL of NADPH-B reagent (BD Gentest) and3.52 microL of water, for CYP 1A2, 2B6, 2C8, 2C9, 2C19 and 2D6. ForCYP3A4, 1.6 microL of 1 M KPO₄, 0.4 microL of NADPH-A reagent and 0.08microL of NADPH-B reagent, and 1.92 microL of water was mixed for eachwell. CYP enzyme mixture was prepared by following mixing ratio: 0.96microL of water, 0.8 microL of 1 M KPO₄, 0.16 microL of Luciferin-ME,CYP1A2 Enzyme 0.08 microL/well for CYP1A2, 1.176 microL of water, 0.8microL of 1 M KPO₄, 0.008 microL of Luciferin-2B6, CYP2B6 Enzyme 0.016microL/well for CYP2B6, 1.04 microL of water, 0.4 microL of 1 M KPO₄,0.24 microL of Luciferin-ME, CYP2C8 Enzyme 0.32 microL/well for CYP2C8,1.56 microL of water, 0.2 microL of 1 M KPO₄, 0.16 microL ofLuciferin-H, CYP2C9 Enzyme 0.08 microL/well for CYP2C9, 1.552 microL ofwater, 0.4 microL of 1 M KPO₄, 0.008 microL of Luciferin-H EGE, CYP2C19Enzyme 0.04 microL/well for CYP2C19, 1.136 microL of water, 0.8 microLof 1 M KPO₄, 0.024 microL of Luciferin-ME EGE, CYP2D6 Enzyme 0.04microL/well for CYP2D6, 1.916 microL of 100 mM Tris-HCl, 0.004 microL ofLuciferin-PPXE, CYP3A4 Enzyme 0.08 microL/well for CYP3A4. Four microLof NADPH-regenerating solution was placed in 384 well plate, and then 2microL of stock solution of test compounds and 2 microL of CYP enzymemixture were added into each well. The plate was spun down and incubatedat each condition as shown in Table 69. After incubation, 8 microL ofLuciferin Detection Reagent for each CYP enzyme was added into each welland stirred by plate shaker (BioShake XP, WAKEN B TECH) at 1000 rpm for1 min. The plate was incubated for 30 min at room temperature, protectedfrom light. Luminescence was measured by luminometer (Ultra, Tecan andEnVision, PerkinElmer). Luminescence signals were used to determinepercent inhibition at 10 microM of test compound. A separate controlincubation for chemiluminescence contained test compound (10 microM) andcontrol CYPs.

TABLE 68 CYP P450-GloAssay Human CYP Enzymes isoforms Kit Cat No. (BDGentest) Cat. No. CYP1A2 V8772 456203 CYP2B6 V8322 456255 CYP2C8 V8782456252 CYP2C9 V8792 456258 CYP2C19 V8882 456259 CYP2D6 V8892 456217CYP3A4 V8912 456202

TABLE 69 Substrate Incubation time CYP Enzyme concentration (min)/isoforms (pmol) (μM) Temperature CYP1A2 0.08 100 45/room temperatureCYP2B6 0.016 3 30/room temperature CYP2C8 0.08 150 90/37° C. CYP2C9 0.08100 30/37° C. CYP2C19 0.04 10 30/room temperature CYP2D6 0.04 30 30/roomtemperature CYP3A4 0.08 25 30/room temperature

The compounds of this invention show preferable results, which show theabove-mentioned practical use.

To summarize the above metabolism assays, all the compounds of thepresent invention show unexpectedly preferable results in the HLM assayand/or in the drug-drug interaction assay comparing with the closestcompounds. Therefore, all the compounds of the present invention haveexcellent pharmacokinetic properties.

hERG assay

The hERG (Human ether-a-go-go-related gene) channel inhibitory activityand the QT prolonging action of the compound of the present inventioncan be confirmed in the suitable methods known to skilled in the art.For example, hERG channel inhibitory activity of compounds of thepresent invention have been confirmed in electrophysiology assay(Chanchin, M. et al., Folia Pharmacol. Jpn., 2002, 119, 345-351).

All tested compounds of the invention show higher IC₅₀ values in hERGassay than IC₅₀ values in P2X7 functional assay described above.

All publications, including but not limited to, issued patents, patentapplications, and journal articles, cited in this application are eachherein incorporated by reference in their entirety. Although theinvention has been described above with reference to the disclosedembodiments, those skilled in the art would readily appreciate that thespecific experiments detailed are only illustrative of the invention. Itshould be understood that various modifications can be made withoutdeparting from the spirit of the invention. Accordingly, the inventionis limited only by the claims.

1-16. (canceled)
 17. A compound represented by the following formula(I):

or a prodrug thereof or a pharmaceutically acceptable salt thereof,wherein: X is N or N-oxide; n is 0 or 1; R¹ is selected from the groupconsisting of: (1) hydrogen, (2) halogen, (3) hydroxyl, (4) —NH₂, (5)—NH-C₁₋₆ alkyl and (6) —S(O)_(m)—C₁₋₆ alkyl; wherein m is independently0, 1 or 2; R² is selected from the group consisting of: (1) hydrogen,(2) halogen, (3) C₁₋₆ alkyl and (4) —O—C₁₋₆ alkyl; wherein the C₁₋₆alkyl or the —O— C₁₋₆ alkyl is unsubstituted or substituted with one ormore substituents independently selected from the group consisting of:halogen, hydroxyl, —O—C₁₋₆ alkyl, —CN, —NR^(9a)R^(10a), —(C═O)—R^(9a),—(C═O)—NR^(9a)R^(10a) and —S(O)_(m)—R^(9a); wherein m is independently0, 1 or 2; R¹ may form ═CH₂ or ═O with R²; or R¹ may form a 3 to 7membered ring with R² which may contain one or more independentlyselected from the group consisting of: nitrogen atom, oxygen atom,sulfur atom and carbonyl group; where the 3 to 7 membered ring isunsubstituted or substituted one or more with C₁₋₆ alkyl; R³ isindependently selected from the group consisting of: (1) hydrogen, (2)halogen, (3) C₁₋₆ alkyl and (4) —O—C₁₋₆ alkyl; p is 0, 1, 2 or 3; when pis 2 or 3, each R³ is the same or different; R⁴ is selected from thegroup consisting of: (1) hydrogen, (2) halogen and (3) hydroxyl; R⁵ ishydrogen or C₁₋₆ alkyl; R⁶ is selected from the group consisting of: (1)hydrogen, (2) C₁₋₆ alkyl, (3) hydroxy C₁₋₆ alkyl, (4) C₁₋₆ alkoxy C₁₋₆alkyl and (5) heterocyclyl C₁₋₆ alkyl; R⁵ may form a saturated 3 to 7membered ring with R⁶ which may contain a nitrogen atom, an oxygen atom,a sulfur atom or a double bond; or a saturated or unsaturated bicyclic 9to 10 membered ring with R⁶ which may contain a nitrogen atom, an oxygenatom or a sulfur atom; wherein the saturated 3 to 7 membered ring or thesaturated or unsaturated bicyclic 9 to 10 membered ring is optionallysubstituted with 1 to 6 substituents independently selected from thegroup consisting of: (1) hydroxyl, (2) halogen, (3) —O-aryl and (4)—O-C₁₋₆ alkylaryl; R^(7a) and R^(7b) are independently selected from thegroup consisting of: (1) hydrogen, (2) halogen, (3) hydroxyl, (4) C₁₋₆alkyl and (5) —NR^(9b)R^(10b); R^(7a) may form a 3 to 7 membered ringwith R⁵ which may contain a nitrogen atom or an oxygen atom; or R^(7a)may form a 3 to 7 membered ring with R^(7b) which may contain a nitrogenatom or an oxygen atom; q is 0 or 1; R⁸ is selected from the groupconsisting of: (1) hydrogen, (2) C₁₋₆ alkyl, (3) —O—C₁₋₆ alkyl, (4) C₂₋₆alkenyl, (5) C₃₋₁₀ cycloalkyl, (6) —NR^(9b)R^(10b): wherein the C₁₋₆alkyl, the —O—C₁₋₆ alkyl, the C₂₋₆ alkenyl, the C₃₋₁₀ cycloalkyl or the—NR^(9b)R^(10b) is unsubstituted or substituted with one or moresubstituents independently selected from the group consisting of:halogen and hydroxyl; (7) heterocyclyl, (8) aryl, (9) —O—C₁₋₆ alkylaryl,(10) —O-aryl, (11) heteroaryl and (12) aryl-substituted heteroaryl:wherein the heterocyclyl, the aryl, the —O—C₁₋₆ alkylaryl, the —O-aryl,the heteroaryl or the aryl-substituted heteroaryl is unsubstituted orsubstituted with one or more substituents independently selected fromthe group consisting of: halogen, hydroxyl, —O—C₁₋₆ alkyl, —O—C₁₋₆haloalkyl, —C₃₋₇ cycloalkyl, —O—C₃₋₇ cycloalkyl, hydroxyl-C₁₋₆ alkoxy,—CN, —NR^(9b)R^(10b), (C═O)—R^(9b), —(C═O)—NR^(9b)R^(10b),—NR^(9b)—(C═O)—R^(10b), —NR¹¹—(C═O)—NR^(9b)R^(10b),—NR^(9b)—(C═O)—OR^(10b), —NR^(9b)—S(O)_(m)—R, —NR¹¹—S(O)_(m)—NR^(9b)R^(10b), S(O)_(m)—R^(9b) and C₁₋₆ alkyl which may be substitutedone or more with halogen, hydroxyl, —O—C₁₋₆ alkyl or NR^(9b)R^(10b);wherein m is independently 0, 1 or 2; R^(9a), R^(9b), R^(10a), R^(10b)or R¹¹ is independently selected from the group consisting of: (1)hydrogen, (2) hydroxyl, (3) C₁₋₆ alkyl and (4) hydroxyC₁₋₆ alkyl; R^(9a)may form a 4 to 7 membered ring with R^(10a) which may contain one ormore independently selected from the group consisting of: nitrogen atom,oxygen atom, sulfur atom and double bond, wherein the 4 to 7 memberedring is optionally substituted with 1 to 6 substituents independentlyselected from the group consisting of: (1) hydroxyl, (2) halogen, (3)C₁₋₆ alkyl and (4) —O—C₁₋₆ alkyl; R^(9b) may form a 4 to 7 membered ringwith R^(10b) which may contain one or more independently selected fromthe group consisting of: nitrogen atom, oxygen atom, sulfur atom anddouble bond, wherein the 4 to 7 membered ring is optionally substitutedwith 1 to 6 substituents independently selected from the groupconsisting of: (1) hydroxyl, (2) halogen and (3) C₁₋₆ alkyl.
 18. Thecompound or a prodrug thereof or a pharmaceutically acceptable saltthereof according to claim 1, wherein: X is N; R⁵ is hydrogen or C₁₋₆alkyl; R⁶ is selected from the group consisting of: (1) hydrogen and (2)C₁₋₆ alkyl; R⁵ may form a saturated or unsaturated bicyclic 9 to 10membered ring with R⁶ which may contain a nitrogen atom, an oxygen atomor a sulfur atom; wherein the saturated or unsaturated bicyclic 9 to 10membered ring is optionally substituted with 1 to 6 substituentsindependently selected from the group consisting of: (1) hydroxyl, (2)halogen and (3) —O-aryl; R^(7a) and R^(7b) are independently selectedfrom the group consisting of: (1) hydrogen, (4) C₁₋₆ alkyl and (5)—NR^(9b)R^(10b); R^(7a) may form a 3 to 7 membered ring with R⁵ whichmay contain a nitrogen atom or an oxygen atom; or R^(7a) may form a 3 to7 membered ring with R^(7b) which may contain a nitrogen atom or anoxygen atom; R⁸ is selected from the group consisting of: (1) hydrogen,(2) C₁₋₆ alkyl, (5) C₃₋₁₀ cycloalkyl, wherein the C₁₋₆ alkyl or theC₃₋₁₀ cycloalkyl is unsubstituted or substituted with one or moresubstituents independently selected from the group consisting of:halogen and hydroxyl; (7) heterocyclyl, (8) aryl, (9) —O—C₁₋₆ alkylaryl,(10) —O-aryl, (11) heteroaryl and (12) aryl-substituted heteroaryl,wherein the heterocyclyl, the aryl, the —O—C₁₋₆ alkylaryl, the —O-aryl,the heteroaryl or the aryl-substituted heteroaryl is unsubstituted orsubstituted with one or more substituents independently selected fromthe group consisting of: halogen, hydroxyl, —O—C₁₋₆ alkyl, —O—C₁₋₆haloalkyl, —CN and C₁₋₆ alkyl which may be substituted one or more withhalogen, hydroxyl, —O—C₁₋₆ alkyl or NR^(9b)R^(10b).
 19. A compoundrepresented by the following formula (M):

or a prodrug thereof or a pharmaceutically acceptable salt thereof,wherein: n is 0 or 1; R¹ is selected from the group consisting of: (1)hydrogen, (2) halogen, (3) hydroxyl, (4) —NH₂, (5) —NH-C-6 alkyl and (6)—S(O)_(m)—C₁₋₆ alkyl; wherein m is independently 0, 1 or 2; R² isselected from the group consisting of: (1) hydrogen, (2) halogen, (3)C₁₋₆ alkyl and (4) —O—C₁₋₆ alkyl; wherein the C₁₋₆ alkyl or the —O—C₁₋₆alkyl is unsubstituted or substituted with one or more substituentsindependently selected from the group consisting of: halogen, hydroxyl,—O—C₁₋₆ alkyl, —CN, —NR^(9a)R^(10a), —(C═O)—R^(9a),—(C═O)—NR^(9a)R^(10a) and —S(O)_(m)—R^(9a); wherein m is independently0, 1 or 2; R¹ may form ═CH₂ or ═O with R²; or R¹ may form a 3 to 7membered ring with R² which may contain one or more independentlyselected from the group consisting of: nitrogen atom, oxygen atom,sulfur atom and carbonyl group; where the 3 to 7 membered ring isunsubstituted or substituted one or more with C₁₋₆ alkyl; R³ isindependently selected from the group consisting of: (1) hydrogen, (2)halogen, (3) C₁₋₆ alkyl and (4) —O—C₁₋₆ alkyl; p is 0, 1, 2 or 3; when pis 2 or 3, each R³ is the same or different; R⁴ is selected from thegroup consisting of: (1) hydrogen, (2) halogen and (3) hydroxyl; R⁵ ishydrogen or C₁₋₆ alkyl; R⁶ is selected from the group consisting of: (1)hydrogen, (2) C₁₋₆ alkyl, (3) hydroxyC₁₋₆ alkyl, (4) C₁₋₆ alkoxy C₁₋₆alkyl and (5) heterocyclyl C₁₋₆ alkyl; R⁵ may form a saturated 3 to 7membered ring with R⁶ which may contain a nitrogen atom, an oxygen atom,a sulfur atom or a double bond; wherein the saturated 3 to 7 memberedring is optionally substituted with 1 to 6 substituents independentlyselected from the group consisting of: (1) hydroxyl, (2) halogen, (3)—O-aryl and (4) —O—C₁₋₆ alkylaryl; R^(9a), R^(9b), R^(10a) or R^(10b) isindependently selected from the group consisting of: (1) hydrogen, (2)hydroxyl, (3) C₁₋₆ alkyl and (4) hydroxyC₁₋₆ alkyl; R^(9a) may form a 4to 7 membered ring with R^(10a) which may contain a nitrogen atom or anoxygen atom; wherein the 4 to 7 membered ring is optionally substitutedwith 1 to 6 substituents independently selected from the groupconsisting of: (1) hydroxyl, (2) halogen, (3) C₁₋₆ alkyl and (4) —O—C₁₋₆alkyl; R^(9b) may form a 4 to 7 membered ring with R^(10b) which maycontain a nitrogen atom or an oxygen atom; wherein the 4 to 7 memberedring is optionally substituted with 1 to 6 substituents independentlyselected from the group consisting of: (1) hydroxyl, (2) halogen and (3)C₁₋₆ alkyl; R¹², R¹³, R¹⁴ and R¹⁵ are independently selected from thegroup consisting of: (1) hydrogen, (2) hydroxyl, (3) halogen, (4) C₁₋₆alkyl, (5) —O—C₁₋₆ alkyl and (6) CN; wherein the C₁₋₆ alkyl or the—O—C₁₋₆ alkyl is unsubstituted or substituted with one or moresubstituents independently selected from the group consisting of:halogen, hydroxyl, —O—C₁₋₆ alkyl and NR^(9b)R^(10b); or R¹² may form a 5to 7 membered ring with R⁵ which may contain one or more independentlyselected from the group consisting of: nitrogen atom and oxygen atom.20. The compound or a prodrug thereof or a pharmaceutically acceptablesalt thereof according to claim 19, wherein: n is 1; R¹ is hydrogen orhydroxyl; R² is methyl which is unsubstituted or substituted with one ormore substituents independently selected from the group consisting of:halogen, hydroxyl, —O—C₁₋₆ alkyl, —CN and —NR^(9a)R^(10a); p is 0; R⁴ ishydrogen or fluoro; R⁵ and R⁶ are independently selected from the groupconsisting of: (1) hydrogen and (2) C₁₋₆ alkyl; R¹², R¹³ and R¹⁴ areindependently selected from the group consisting of: (1) hydrogen, (3)halogen, and (4) C₁₋₃ alkyl which may be substituted one or more withhydroxyl; R¹⁵ is hydrogen.
 21. A compound which is selected from thegroup following or a prodrug thereof or a pharmaceutically acceptablesalt thereof,N-(2,4-dichloro-6-methylbenzyl)-8-oxo-5,6,7,8-tetrahydroquinoline-5-carboxamide;N-(2-chloro-3-(trifluoromethyl)benzyl)-8-oxo-5,6,7,8-tetrahydroquinoline-5-carboxamide;N-(2,3-dichlorobenzyl)-8-oxo-5,6,7,8-tetrahydroquinoline-5-carboxamide;N-(2,4-dichloro-6-(hydroxymethyl)benzyl)-8-oxo-5,6,7,8-tetrahydroquinoline-5-carboxamide;N-(cycloheptylmethyl)-8-oxo-5,6,7,8-tetrahydroquinoline-5-carboxamide;N-(2,4-dichloro-6-methylbenzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;N-(2-chloro-3-(trifluoromethyl)benzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;N-(2,3-dichlorobenzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;N-(2,4-dichloro-6-(hydroxymethyl)benzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;N-(2,4-dichloro-6-(methoxymethyl)benzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;N-(2,4-dichloro-6-methylbenzyl)-7-methylene-6,7-dihydro-5H-cyclopenta[b]pyridine-5-carboxamide;N-(2,4-dichloro-6-methylbenzyl)-5-fluoro-8-oxo-5,6,7,8-tetrahydroquinoline-5-carboxamide;N-(2-chloro-3-(trifluoromethyl)benzyl)-5-fluoro-8-oxo-5,6,7,8-tetrahydroquinoline-5-carboxamide;N-(2,4-dichloro-6-(hydroxymethyl)benzyl)-5-fluoro-8-oxo-5,6,7,8-tetrahydroquinoline-5-carboxamide;N-(2,4-dichloro-6-methylbenzyl)-5-hydroxy-8-oxo-5,6,7,8-tetrahydroquinoline-5-carboxamide;N-(2,4-dichloro-6-methylbenzyl)-7-oxo-6,7-dihydro-5H-cyclopenta[b]pyridine-5-carboxamide;N-(2-chloro-3-(trifluoromethyl)benzyl)-7-oxo-6,7-dihydro-5H-cyclopenta[b]pyridine-5-carboxamide;N-(2,4-dichloro-6-methylbenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;N-(2-chloro-3-(trifluoromethyl)benzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;N-(2,4-dichloro-6-(hydroxymethyl)benzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;N-(2,3-dichlorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;N-(2,4-dichlorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;N-(2,4-dichloro-6-(methoxymethyl)benzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;N-(2,4-dichloro-6-methylbenzyl)-5,8-dihydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;N-(2-chloro-3-(trifluoromethyl)benzyl)-5,8-dihydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;N-(2,4-dichloro-6-methylbenzyl)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridine-5-carboxamide;N-(2-chloro-3-(trifluoromethyl)benzyl)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridine-5-carboxamide;N-(2,3-dichlorobenzyl)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridine-5-carboxamide;N-(2,4-dichlorobenzyl)-5-fluoro-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridine-5-carboxamide;2-(5-((2,4-dichloro-6-methylbenzyl)carbamoyl)-5,6,7,8-tetrahydroquinolin-8-yl)aceticacid;2-(5-((2-chloro-3-(trifluoromethyl)benzyl)carbamoyl)-5,6,7,8-tetrahydroquinolin-8-yl)aceticacid;(2-amino-2-oxoethyl)-N-(2-chloro-3-(trifluoromethyl)benzyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;N-(2,4-dichloro-6-methylbenzyl)-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;N-(2,4-dichloro-6-methylbenzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;N-(2-chloro-3-(trifluoromethyl)benzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;N-(2,3-dichlorobenzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;N-(2,4-dichlorobenzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;N-(2,4-dichlorobenzyl)-5-fluoro-7-hydroxy-7-(hydroxymethyl)-6,7-dihydro-5H-cyclopenta[b]pyridine-5-carboxamide;N-(2,4-dichloro-6-methylbenzyl)-5-fluoro-8-hydroxy-8-(methoxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;N-(2-chloro-3-(trifluoromethyl)benzyl)-5-fluoro-8-hydroxy-8-(methoxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S*,8S*)-N-(2,4-dichlorobenzyl)-5-fluoro-8-hydroxy-8-(methoxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S*,8S*)-N-(2-chloro-4-fluorobenzyl)-5-fluoro-8-hydroxy-8-(methoxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;8-(aminomethyl)-N-(2,4-dichloro-6-methylbenzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;N-(2,4-dichloro-6-methylbenzyl)-8-hydroxy-8-((methylamino)methyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;8-(aminomethyl)-N-(2,4-dichloro-6-methylbenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;N-(2,4-dichloro-6-methylbenzyl)-5-fluoro-8-hydroxy-8-((methylamino)methyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;N-(2,4-dichloro-6-methylbenzyl)-8-((dimethylamino)methyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;8-(aminomethyl)-N-(2-chloro-3-(trifluoromethyl)benzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;N-(2-chloro-3-(trifluoromethyl)benzyl)-5-fluoro-8-hydroxy-8-((methylamino)methyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;N-(2-chloro-3-(trifluoromethyl)benzyl)-8-((dimethylamino)methyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S*,8R*)-N-(2,4-dichlorobenzyl)-5-fluoro-8-hydroxy-8-((3-hydroxyazetidin-1-yl)methyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S*,8R*)-N-(2-chloro-4-fluorobenzyl)-5-fluoro-8-hydroxy-8-((3-hydroxyazetidin-1-yl)methyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S*,8R*)-N-(2-chloro-4-fluorobenzyl)-5-fluoro-8-hydroxy-8-((3-methoxyazetidin-1-yl)methyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S*,8R*)-N-(2-chloro-4-fluorobenzyl)-5-fluoro-8-hydroxy-8-((3-hydroxy-3-methylazetidin-1-yl)methyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S*,8R*)-N-(2-chloro-4-fluorobenzyl)-5-fluoro-8-hydroxy-8-((3-methoxy-3-methylazetidin-1-yl)methyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S*,8R*)-N-(2-chloro-4-fluorobenzyl)-5-fluoro-8-hydroxy-8-(((2-hydroxyethyl)amino)methyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S*,8R*)-N-(2-chloro-4-fluorobenzyl)-5-fluoro-8-hydroxy-8-(((2-hydroxyethyl)(methyl)amino)methyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;N-(2-chloro-3-(trifluoromethyl)benzyl)-5-fluoro-8-hydroxy-8-methyl-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S*,8R*)-8-amino-N-(2,4-dichlorobenzyl)-5-fluoro-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S*,8S*)-8-amino-N-(2,4-dichlorobenzyl)-5-fluoro-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(3R*,5'S*)-N-(2,4-dichlorobenzyl)-5′-fluoro-5-oxo-6′,7′-dihydro-5′H-spiro[morpholine-3,8′-quinoline]-5′-carboxamide;(3S*,5'S*)-N-(2,4-dichlorobenzyl)-5′-fluoro-5-oxo-6′,7′-dihydro-5′H-spiro[morpholine-3,8′-quinoline]-5′-carboxamide;(5S,8S)-N-(2,4-dichloro-6-methylbenzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8S)-N-(2,4-dichloro-6-methylbenzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2,4-dichlorobenzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8S)-N-(2,4-dichlorobenzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-4-fluorobenzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8S)-N-(2-chloro-4-fluorobenzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2,4-dichloro-6-fluorobenzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8S)-N-(2,4-dichloro-6-fluorobenzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-8-hydroxy-N-(2,3,4-trifluorobenzyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8S)-8-hydroxy-N-(2,3,4-trifluorobenzyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8S)-8-hydroxy-N-(2,4,6-trifluorobenzyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8S)-N-(2,4-difluorobenzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(4-fluoro-2-(trifluoromethyl)benzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8S)-N-(4-fluoro-2-(trifluoromethyl)benzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(4-chloro-2-fluorobenzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8S)-N-(4-chloro-2-fluorobenzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(4-bromo-2-fluorobenzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8S)-N-(4-bromo-2-fluorobenzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-3,4-difluorobenzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8S)-N-(2-chloro-3,4-difluorobenzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,7S)-N-(2,4-dichloro-6-methylbenzyl)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridine-5-carboxamide;(5R,8R)-N-(2,4-dichloro-6-methylbenzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-N-(2,4-dichloro-6-methylbenzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-3-(trifluoromethyl)benzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8R)-N-(2,4-dichlorobenzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-N-(2,4-dichlorobenzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8R)-N-(2-chloro-4-fluorobenzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-N-(2-chloro-4-fluorobenzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8R)-N-(2,4-dichloro-6-fluorobenzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-N-(2,4-dichloro-6-fluorobenzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8R)-8-hydroxy-N-(2,3,4-trifluorobenzyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-8-hydroxy-N-(2,3,4-trifluorobenzyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8R)-N-(4-chloro-2-fluorobenzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-N-(4-chloro-2-fluorobenzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,7R)-N-(2,4-dichloro-6-methylbenzyl)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridine-5-carboxamide;(5S,7R)-N-(2,4-dichloro-6-methylbenzyl)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridine-5-carboxamide;(5R,8S)-N-(2,4-dichloro-6-methylbenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-N-(2,4-dichloro-6-methylbenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8S)-N-(2-chloro-3-(trifluoromethyl)benzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-N-(2-chloro-3-(trifluoromethyl)benzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8S)-N-(2,4-dichloro-6-(hydroxymethyl)benzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-N-(2,4-dichloro-6-(hydroxymethyl)benzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8S)-N-(2,4-dichlorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-N-(2,4-dichlorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-N-(2-chloro-4-fluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-5-fluoro-8-hydroxy-N-(2,3,4-trifluorobenzyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-N-(2,4-difluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-5-fluoro-N-(4-fluoro-2-(trifluoromethyl)benzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-N-(4-chloro-2-fluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8S)-N-(2,6-dichloro-4-(trifluoromethyl)benzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-N-(2,6-dichloro-4-(trifluoromethyl)benzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8S)-N-(2,4-dichloro-6-(difluoromethyl)benzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-N-(2,4-dichloro-6-(difluoromethyl)benzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8S)-N-(2,4-dichloro-6-fluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-N-(2,4-dichloro-6-fluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-N-(4-bromo-2-chlorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-N-((R)-1-(2,4-dichlorophenyl)ethyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8S)-N-(2,3-dichlorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-N-(2,3-dichlorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-N-(2-chloro-6-methylbenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-N-(2-chloro-4,5-difluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-5-fluoro-8-hydroxy-N-(2,3,6-trichlorobenzyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-N-(2-chloro-4-methylbenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8R)-N-(2,4-dichloro-6-methylbenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2,4-dichloro-6-methylbenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8R)-N-(2-chloro-3-(trifluoromethyl)benzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-3-(trifluoromethyl)benzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8R)-N-(2,4-dichloro-6-(hydroxymethyl)benzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2,4-dichloro-6-(hydroxymethyl)benzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8R)-N-(2,4-dichlorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2,4-dichlorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8R)-N-(2-chloro-4-fluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-4-fluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8R)-5-fluoro-8-hydroxy-N-(2,3,4-trifluorobenzyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-5-fluoro-8-hydroxy-N-(2,3,4-trifluorobenzyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8R)-N-(2,6-dichlorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2,6-dichlorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8R)-N-(2,4-difluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2,4-difluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-6-fluoro-3-methylbenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8R)-5-fluoro-N-(4-fluoro-2-(trifluoromethyl)benzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-5-fluoro-N-(4-fluoro-2-(trifluoromethyl)benzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8R)-N-(4-chloro-2-fluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(4-chloro-2-fluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8R)-N-(2,6-dichloro-4-(trifluoromethyl)benzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2,6-dichloro-4-(trifluoromethyl)benzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2,4-dichloro-6-(difluoromethyl)benzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-4-fluoro-6-(hydroxymethyl)benzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8R)-N-(2,4-dichloro-6-fluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2,4-dichloro-6-fluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8R)-N-(4-bromo-2-chlorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(4-bromo-2-chlorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8R)-N-((R)-1-(2,4-dichlorophenyl)ethyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8R)-N-(4-chloro-2-(trifluoromethyl)benzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(4-chloro-2-(trifluoromethyl)benzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8R)-N-(2,3-dichlorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2,3-dichlorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8R)-N-(2-chloro-6-methylbenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-6-methylbenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8R)-N-(2-chloro-4,5-difluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-4,5-difluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8R)-5-fluoro-8-hydroxy-N-(2,3,6-trichlorobenzyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-5-fluoro-8-hydroxy-N-(2,3,6-trichlorobenzyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8R)-N-(2-chloro-4-methylbenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-4-methylbenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-5-fluoro-8-hydroxy-N-((S)-1-(2,3,4-trichlorophenyl)ethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-3-fluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-3,6-difluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-6-fluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-4-methoxybenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2,5-dichlorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-3,4-difluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-5-fluoro-N-(2-fluoro-3-(trifluoromethyl)benzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-4,6-difluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-((3,5-dichloropyridin-2-yl)methyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-5-fluoro-N-(3-fluoro-2-(trifluoromethyl)benzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-6-(trifluoromethyl)benzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-5-fluoro-8-hydroxy-N-(2,4,6-trifluorobenzyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(5-bromo-2-chlorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(4-bromo-2-fluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(4-chloro-2,3-difluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(4-chloro-2,6-difluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(3-chloro-2,4-difluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-5-fluoro-N-(2-fluoro-6-(trifluoromethyl)benzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-4-(trifluoromethyl)benzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(3-chloro-4-fluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-5-fluoro-8-hydroxy-N-((R)-1,2,3,4-tetrahydronaphthalen-1-yl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(3-chloro-2-fluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2,4-dichlorophenethyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-5-fluoro-8-hydroxy-N-((1-morpholinocyclohexyl)methyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(3-chloro-2,6-difluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-((3-chloro-5-(trifluoromethyl)pyridin-2-yl)methyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chlorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-((R)-2,3-dihydro-1H-inden-1-yl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(3,4-dichlorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-6-methoxybenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-5-fluoro-8-hydroxy-N-(2-(trifluoromethyl)benzyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-5-fluoro-8-hydroxy-N-(3,4,5-trifluorobenzyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(4-cyano-2-fluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(3,4-difluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(3-chloro-5-fluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide(5S,8S)-N-(2-chloro-5-fluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(3-chlorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(4-chloro-3-fluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-5-fluoro-N-(2-fluoro-4-(trifluoromethoxy)benzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2,3-difluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-5-(trifluoromethyl)benzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(4-chlorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-5-fluoro-8-hydroxy-N-(4-methoxy-2-(trifluoromethyl)benzyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(3,5-dichlorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-((4-(4-chlorophenyl)thiazol-2-yl)methyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-5-fluoro-8-hydroxy-N-(2-(morpholinomethyl)benzyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-5-fluoro-8-hydroxy-N-((1S,2R)-2-phenylcyclopropyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(6-chloro-2-fluoro-3-methylbenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2,6-difluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-5-fluoro-8-hydroxy-N-((S)-1,2,3,4-tetrahydronaphthalen-1-yl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-5-fluoro-8-hydroxy-N-(2-(3-(trifluoromethyl)phenoxy)ethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-5-fluoro-N-((1-(4-fluorophenyl)cyclopropyl)methyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(3,5-difluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-5-fluoro-8-hydroxy-N-((1R,2S)-2-phenylcyclopropyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-5-fluoro-N-(2-fluorobenzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-3-methoxybenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-((S)-2,3-dihydro-1H-inden-1-yl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(3,3-dimethylbutyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-5-fluoro-8-hydroxy-N-(2-phenoxyethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(4,6-dichloro-2,3-dihydrobenzofuran-3-yl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(5,7-dichlorochroman-4-yl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(1-(adamantan-1-yl)ethyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-(4-chlorophenyl)-2-(4,4-difluoropiperidin-1-yl)ethyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(chroman-3-yl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-(4-chlorophenyl)propyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-5-fluoro-8-hydroxy-N-(2-morpholino-2-phenylethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-(4,4-difluoropiperidin-1-yl)-2-(4-methylthiazol-5-yl)ethyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-((R)-1-(2-chloro-4-fluorophenyl)ethyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-((trans)-2-(2,4-dichlorophenyl)cyclopropyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-((S)-1-(2-chloro-4-fluorophenyl)ethyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-((4-(2,4-dichlorophenyl)tetrahydro-2H-pyran-4-yl)methyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2,4-dichlorobenzyl)-3,5-difluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-4-fluorobenzyl)-3,5-difluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2,4-dichlorobenzyl)-5-fluoro-8-hydroxy-3-methyl-5,6,7,8-tetrahydroquinoline-5-carboxamide(5S,8S)-N-(2-chloro-4-fluorobenzyl)-5-fluoro-8-hydroxy-3-methyl-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-5-((2,4-dichlorobenzyl)carbamoyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline1-oxide;(R)-N-(2-chloro-3-(trifluoromethyl)benzyl)-5-fluoro-8-oxo-5,6,7,8-tetrahydroquinoline-5-carboxamide;(S)-N-(2-chloro-3-(trifluoromethyl)benzyl)-5-fluoro-8-oxo-5,6,7,8-tetrahydroquinoline-5-carboxamide;(S)-N-(2,4-dichlorobenzyl)-5-fluoro-8-oxo-5,6,7,8-tetrahydroquinoline-5-carboxamide;(S)-N-(2-chloro-4-fluorobenzyl)-5-fluoro-8-oxo-5,6,7,8-tetrahydroquinoline-5-carboxamide;(S)-N-(2-chloro-3-fluorobenzyl)-5-fluoro-8-oxo-5,6,7,8-tetrahydroquinoline-5-carboxamide;(S)-N-(2,4-dichloro-6-fluorobenzyl)-5-fluoro-8-oxo-5,6,7,8-tetrahydroquinoline-5-carboxamide;(S)-N-(2,3-dichlorobenzyl)-5-fluoro-8-oxo-5,6,7,8-tetrahydroquinoline-5-carboxamide;(S)-N-(2-chloro-4-(trifluoromethyl)benzyl)-5-fluoro-8-oxo-5,6,7,8-tetrahydroquinoline-5-carboxamide;(S)-5-fluoro-8-oxo-N-(2,3,4-trifluorobenzyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(S)-N-((3,5-dichloropyridin-2-yl)methyl)-5-fluoro-8-oxo-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2,4-dichlorobenzyl)-5-fluoro-8-hydroxy-8-methyl-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-N-(2,4-dichlorobenzyl)-5-fluoro-8-hydroxy-8-methyl-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-5-fluoro-8-hydroxy-8-methyl-N-(2,3,4-trifluorobenzyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-4-fluorobenzyl)-5-fluoro-8-hydroxy-8-methyl-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-N-(2-chloro-4-fluorobenzyl)-5-fluoro-8-hydroxy-8-methyl-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2,4-dichloro-6-(hydroxymethyl)benzyl)-5-fluoro-8-hydroxy-8-methyl-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-4-fluoro-6-(hydroxymethyl)benzyl)-5-fluoro-8-hydroxy-8-methyl-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2,4-difluorobenzyl)-5-fluoro-8-hydroxy-8-methyl-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(4-chloro-2-fluorobenzyl)-5-fluoro-8-hydroxy-8-methyl-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2,4-dichloro-6-fluorobenzyl)-5-fluoro-8-hydroxy-8-methyl-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-4,6-difluorobenzyl)-5-fluoro-8-hydroxy-8-methyl-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(4-chloro-2,3-difluorobenzyl)-5-fluoro-8-hydroxy-8-methyl-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(3-chloro-2,4-difluorobenzyl)-5-fluoro-8-hydroxy-8-methyl-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(4-chloro-2,6-difluorobenzyl)-5-fluoro-8-hydroxy-8-methyl-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-((R)-1-(2-chloro-4-fluorophenyl)ethyl)-5-fluoro-8-hydroxy-8-methyl-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-((S)-1-(2-chloro-4-fluorophenyl)ethyl)-5-fluoro-8-hydroxy-8-methyl-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-((3,5-dichloropyridin-2-yl)methyl)-5-fluoro-8-hydroxy-8-methyl-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-((trans)-2-(2,4-dichlorophenyl)cyclopropyl)-5-fluoro-8-hydroxy-8-methyl-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-5-fluoro-8-hydroxy-8-methyl-N-((1-morpholinocyclohexyl)methyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-5-fluoro-8-hydroxy-8-methyl-N-((1-morpholinocyclohexyl)methyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-4-fluorobenzyl)-5-fluoro-8-hydroxy-3,8-dimethyl-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-N-(2,4-dichlorobenzyl)-5-fluoro-8-hydroxy-8-(((2-hydroxyethyl)(methyl)amino)methyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8S)-N-(2,4-dichlorobenzyl)-5-fluoro-8-hydroxy-8-(((2-hydroxyethyl)(methyl)amino)methyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8S)-N-(2,4-dichlorobenzyl)-5-fluoro-8-hydroxy-8-((3-hydroxyazetidin-1-yl)methyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-8-(cyanomethyl)-N-(2,4-dichlorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-N-(2-chloro-4-fluorobenzyl)-8-(cyanomethyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-4-fluorobenzyl)-8-(cyanomethyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-8-(cyanomethyl)-N-(2,4-dichloro-6-(hydroxymethyl)benzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-N-(2-chloro-4-fluoro-6-(hydroxymethyl)benzyl)-8-(cyanomethyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2,4-dichlorobenzyl)-5-fluoro-8-(fluoromethyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-4-fluorobenzyl)-5-fluoro-8-(fluoromethyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2,4-dichlorobenzyl)-5-fluoro-8-hydroxy-8-((methylthio)methyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-4-fluorobenzyl)-5-fluoro-8-hydroxy-8-((methylthio)methyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-4-fluorobenzyl)-5-fluoro-8-hydroxy-8-(((2-hydroxyethyl)thio)methyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(2R,5'S)-N-(2,4-dichlorobenzyl)-5′-fluoro-4-methyl-6′,7′-dihydro-5′H-spiro[morpholine-2,8′-quinoline]-5′-carboxamide;(5S,5'S)-N-(2,4-dichlorobenzyl)-5′-fluoro-2-oxo-6′,7′-dihydro-5′H-spiro[oxazolidine-5,8′-quinoline]-5′-carboxamide;(5R,5'S)-N-(2,4-dichlorobenzyl)-5′-fluoro-2-oxo-6′,7′-dihydro-5′H-spiro[oxazolidine-5,8′-quinoline]-5′-carboxamide;(2S,5′R)-N-(2,4-dichlorobenzyl)-5′-fluoro-5-oxo-6′,7′-dihydro-5′H-spiro[morpholine-2,8′-quinoline]-5′-carboxamide;(2S,5'S)-N-(2,4-dichlorobenzyl)-5′-fluoro-5-oxo-6′,7′-dihydro-5′H-spiro[morpholine-2,8′-quinoline]-5′-carboxamide;(2R,5'S)-N-(2,4-dichlorobenzyl)-5′-fluoro-5-oxo-6′,7′-dihydro-5′H-spiro[morpholine-2,8′-quinoline]-5′-carboxamide;(5S,8S)-N-(2-chloro-4-fluorobenzyl)-5-fluoro-8-hydroxy-8-((methylsulfinyl)methyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-N-(2,4-dichlorobenzyl)-5-fluoro-8-hydroxy-8-((methylthio)methyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2,4-dichlorobenzyl)-5-fluoro-8-hydroxy-8-((methylsulfonyl)methyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-4-fluorobenzyl)-5-fluoro-8-hydroxy-8-((methylsulfonyl)methyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2,4-dichlorobenzyl)-5-fluoro-8-hydroxy-8-(((2-hydroxyethyl)sulfonyl)methyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-4-fluorobenzyl)-5-fluoro-8-hydroxy-8-(((2-hydroxyethyl)sulfonyl)methyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8R)-N-(2,4-dichlorobenzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8S)-N-(2,4-dichlorobenzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2,4-dichlorobenzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-N-(2,4-dichlorobenzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-4-fluorobenzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-N-(2-chloro-4-fluorobenzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-N-(2,3,4-trifluorobenzyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-N-(2,3,4-trifluorobenzyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2,4-dichloro-6-fluorobenzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-N-(2,4-dichloro-6-fluorobenzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-3,4-difluorobenzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-N-(2-chloro-3,4-difluorobenzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(4-chloro-2-fluorobenzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-N-(4-chloro-2-fluorobenzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2,4-dichloro-6-(hydroxymethyl)benzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-4-fluoro-6-(hydroxymethyl)benzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2,4-difluorobenzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2,4-dichloro-3-fluorobenzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2,3-dichloro-4-fluorobenzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-4,6-difluorobenzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(4-chloro-2,3-difluorobenzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(3-chloro-2,4-difluorobenzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(4-chloro-2,6-difluorobenzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2,4-dichlorobenzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-3-methyl-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-((R)-1-(2,4-dichlorophenyl)ethyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-((R)-1-(2-chloro-4-fluorophenyl)ethyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-N-((R)-1-(2-chloro-4-fluorophenyl)ethyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-((3,5-dichloropyridin-2-yl)methyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2,4-dichlorophenethyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-((trans)-2-(2,4-dichlorophenyl)cyclopropyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-((4-(2,4-dichlorophenyl)tetrahydro-2H-pyran-4-yl)methyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8S)-N-(2,4-dichloro-6-(hydroxymethyl)benzyl)-5-fluoro-8-methoxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-N-(2,4-dichloro-6-(hydroxymethyl)benzyl)-5-fluoro-8-methoxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2,4-dichloro-6-fluorobenzyl)-5-fluoro-8-methoxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2,3-dichlorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-4-fluorobenzyl)-5-fluoro-8-methoxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-4-(trifluoromethyl)benzyl)-5-fluoro-8-methoxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-5-fluoro-8-methoxy-N-(2,3,4-trifluorobenzyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(4-chloro-2-fluorobenzyl)-5-fluoro-8-methoxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-5-fluoro-8-methoxy-N-(2,4,6-trifluorobenzyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2,4-difluorobenzyl)-5-fluoro-8-methoxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2,4-dichloro-6-(hydroxymethyl)benzyl)-5-fluoro-8-(2-hydroxyethoxy)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-4-fluorobenzyl)-5-fluoro-8-(2-hydroxyethoxy)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-5-fluoro-8-(2-hydroxyethoxy)-N-(2,3,4-trifluorobenzyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(4-chloro-2-fluorobenzyl)-5-fluoro-8-(2-hydroxyethoxy)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2,4-difluorobenzyl)-5-fluoro-8-(2-hydroxyethoxy)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8R)-N-(2,4-dichlorobenzyl)-5-fluoro-8-(2-hydroxyethoxy)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2,4-dichlorobenzyl)-8-(2,3-dihydroxypropoxy)-5-fluoro-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8rac)-N-(2,4-dichlorobenzyl)-5-fluoro-8-(methylsulfonyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8rac)-N-(2,4-dichlorobenzyl)-5-fluoro-8-((2-hydroxyethyl)sulfonyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8S)-N-(2-chloro-3-(trifluoromethyl)benzyl)-5,8-difluoro-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8S)-N-(2,4-dichlorobenzyl)-5,8-difluoro-5,6,7,8-tetrahydroquinoline-5-carboxamideand(5R,8S)-N-(2,3-dichlorobenzyl)-5,8-difluoro-5,6,7,8-tetrahydroquinoline-5-carboxamide.22. The compound according to claim 21, which is selected from the groupfollowing or a prodrug thereof or a pharmaceutically acceptable saltthereof,N-(2,3-dichlorobenzyl)-8-oxo-5,6,7,8-tetrahydroquinoline-5-carboxamide;N-(2,4-dichloro-6-(hydroxymethyl)benzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;N-(2-chloro-3-(trifluoromethyl)benzyl)-7-oxo-6,7-dihydro-5H-cyclopenta[b]pyridine-5-carboxamide;N-(2,4-dichloro-6-methylbenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;N-(2-chloro-3-(trifluoromethyl)benzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;N-(2,4-dichloro-6-(hydroxymethyl)benzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;N-(2,3-dichlorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;N-(2,4-dichlorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;N-(2-chloro-3-(trifluoromethyl)benzyl)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridine-5-carboxamide;N-(2,4-dichlorobenzyl)-5-fluoro-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridine-5-carboxamide;2-(5-((2,4-dichloro-6-methylbenzyl)carbamoyl)-5,6,7,8-tetrahydroquinolin-8-yl)aceticacid;2-(5-((2-chloro-3-(trifluoromethyl)benzyl)carbamoyl)-5,6,7,8-tetrahydroquinolin-8-yl)aceticacid;N-(2-chloro-3-(trifluoromethyl)benzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;N-(2,3-dichlorobenzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;N-(2,4-dichlorobenzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;N-(2,4-dichlorobenzyl)-5-fluoro-7-hydroxy-7-(hydroxymethyl)-6,7-dihydro-5H-cyclopenta[b]pyridine-5-carboxamide;(5S*,8S*)-N-(2-chloro-4-fluorobenzyl)-5-fluoro-8-hydroxy-8-(methoxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;N-(2,4-dichloro-6-methylbenzyl)-8-((dimethylamino)methyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S*,8R*)-N-(2,4-dichlorobenzyl)-5-fluoro-8-hydroxy-8-((3-hydroxyazetidin-1-yl)methyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S*,8R*)-N-(2-chloro-4-fluorobenzyl)-5-fluoro-8-hydroxy-8-hydroxyazetidin-1-yl)methyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S*,8R*)-N-(2-chloro-4-fluorobenzyl)-5-fluoro-8-hydroxy-8-((3-methoxyazetidin-1-yl)methyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S*,8R*)-N-(2-chloro-4-fluorobenzyl)-5-fluoro-8-hydroxy-8-((3-hydroxy-3-methylazetidin-1-yl)methyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S*,8R*)-N-(2-chloro-4-fluorobenzyl)-5-fluoro-8-hydroxy-8-((3-methoxy-3-methylazetidin-1-yl)methyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S*,8R*)-N-(2-chloro-4-fluorobenzyl)-5-fluoro-8-hydroxy-8-(((2-hydroxyethyl)amino)methyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S*,8R*)-N-(2-chloro-4-fluorobenzyl)-5-fluoro-8-hydroxy-8-(((2-hydroxyethyl)(methyl)amino)methyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(3R*,5'S*)-N-(2,4-dichlorobenzyl)-5′-fluoro-5-oxo-6′,7′-dihydro-5′H-spiro[morpholine-3,8′-quinoline]-5′-carboxamide;(3S*,5'S*)-N-(2,4-dichlorobenzyl)-5′-fluoro-5-oxo-6′,7′-dihydro-5′H-spiro[morpholine-3,8′-quinoline]-5′-carboxamide;(5S,8S)-N-(2,4-dichloro-6-methylbenzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2,4-dichlorobenzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-4-fluorobenzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8S)-N-(2-chloro-4-fluorobenzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2,4-dichloro-6-fluorobenzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-8-hydroxy-N-(2,3,4-trifluorobenzyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8S)-8-hydroxy-N-(2,3,4-trifluorobenzyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8S)-8-hydroxy-N-(2,4,6-trifluorobenzyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8S)-N-(2,4-difluorobenzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(4-fluoro-2-(trifluoromethyl)benzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8S)-N-(4-fluoro-2-(trifluoromethyl)benzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(4-chloro-2-fluorobenzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8S)-N-(4-chloro-2-fluorobenzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(4-bromo-2-fluorobenzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8S)-N-(4-bromo-2-fluorobenzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-3,4-difluorobenzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8R)-N-(2,4-dichloro-6-methylbenzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-3-(trifluoromethyl)benzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8R)-N-(2-chloro-4-fluorobenzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-N-(2-chloro-4-fluorobenzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8R)-N-(2,4-dichloro-6-fluorobenzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8R)-8-hydroxy-N-(2,3,4-trifluorobenzyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-8-hydroxy-N-(2,3,4-trifluorobenzyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8R)-N-(4-chloro-2-fluorobenzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8S)-N-(2,4-dichloro-6-methylbenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8S)-N-(2,4-dichloro-6-(hydroxymethyl)benzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8S)-N-(2,4-dichlorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-N-(2,4-dichlorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-N-(2-chloro-4-fluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-5-fluoro-8-hydroxy-N-(2,3,4-trifluorobenzyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-N-(2,4-difluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-5-fluoro-N-(4-fluoro-2-(trifluoromethyl)benzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-N-(4-chloro-2-fluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8S)-N-(2,6-dichloro-4-(trifluoromethyl)benzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-N-(2,6-dichloro-4-(trifluoromethyl)benzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8S)-N-(2,4-dichloro-6-fluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-N-(2,4-dichloro-6-fluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-N-(4-bromo-2-chlorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8S)-N-(2,3-dichlorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-N-(2,3-dichlorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-N-(2-chloro-6-methylbenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-N-(2-chloro-4,5-difluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-N-(2-chloro-4-methylbenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8R)-N-(2,4-dichloro-6-methylbenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8R)-N-(2-chloro-3-(trifluoromethyl)benzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8R)-N-(2,4-dichloro-6-(hydroxymethyl)benzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2,4-dichloro-6-(hydroxymethyl)benzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8R)-N-(2,4-dichlorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2,4-dichlorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8R)-N-(2-chloro-4-fluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-4-fluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8R)-5-fluoro-8-hydroxy-N-(2,3,4-trifluorobenzyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-5-fluoro-8-hydroxy-N-(2,3,4-trifluorobenzyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8R)-N-(2,6-dichlorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8R)-N-(2,4-difluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2,4-difluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8R)-5-fluoro-N-(4-fluoro-2-(trifluoromethyl)benzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-5-fluoro-N-(4-fluoro-2-(trifluoromethyl)benzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8R)-N-(4-chloro-2-fluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(4-chloro-2-fluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8R)-N-(2,6-dichloro-4-(trifluoromethyl)benzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2,4-dichloro-6-(difluoromethyl)benzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-4-fluoro-6-(hydroxymethyl)benzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8R)-N-(2,4-dichloro-6-fluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2,4-dichloro-6-fluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8R)-N-(4-bromo-2-chlorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(4-bromo-2-chlorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8R)-N-(2,3-dichlorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2,3-dichlorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8R)-N-(2-chloro-6-methylbenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8R)-N-(2-chloro-4,5-difluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8R)-5-fluoro-8-hydroxy-N-(2,3,6-trichlorobenzyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8R)-N-(2-chloro-4-methylbenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-4-methylbenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-3-fluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-3,6-difluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-6-fluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-4-methoxybenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-3,4-difluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-4,6-difluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-5-fluoro-N-(3-fluoro-2-(trifluoromethyl)benzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-5-fluoro-8-hydroxy-N-(2,4,6-trifluorobenzyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(4-bromo-2-fluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(4-chloro-2,3-difluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(4-chloro-2,6-difluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-4-(trifluoromethyl)benzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(3-chloro-4-fluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-5-fluoro-8-hydroxy-N-((R)-1,2,3,4-tetrahydronaphthalen-1-yl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(3-chloro-2-fluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(3-chloro-2,6-difluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-((3-chloro-5-(trifluoromethyl)pyridin-2-yl)methyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chlorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-((R)-2,3-dihydro-1H-inden-1-yl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(3,4-dichlorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-5-fluoro-8-hydroxy-N-(2-(trifluoromethyl)benzyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-5-fluoro-8-hydroxy-N-(3,4,5-trifluorobenzyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(4-cyano-2-fluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(3,4-difluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(3-chloro-5-fluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-5-fluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(3-chlorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(4-chloro-3-fluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-5-fluoro-N-(2-fluoro-4-(trifluoromethoxy)benzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2,3-difluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(4-chlorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(3,5-dichlorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-5-fluoro-8-hydroxy-N-((1S,2R)-2-phenylcyclopropyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2,6-difluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-5-fluoro-8-hydroxy-N-((S)-1,2,3,4-tetrahydronaphthalen-1-yl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-5-fluoro-8-hydroxy-N-(2-(3-(trifluoromethyl)phenoxy)ethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(3,5-difluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-5-fluoro-8-hydroxy-N-((1R,2S)-2-phenylcyclopropyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-5-fluoro-N-(2-fluorobenzyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-3-methoxybenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-((S)-2,3-dihydro-1H-inden-1-yl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(3,3-dimethylbutyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-5-fluoro-8-hydroxy-N-(2-phenoxyethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(4,6-dichloro-2,3-dihydrobenzofuran-3-yl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(chroman-3-yl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-5-fluoro-8-hydroxy-N-(2-morpholino-2-phenylethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-(4,4-difluoropiperidin-1-yl)-2-(4-methylthiazol-5-yl)ethyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-((trans)-2-(2,4-dichlorophenyl)cyclopropyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2,4-dichlorobenzyl)-5-fluoro-8-hydroxy-3-methyl-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-4-fluorobenzyl)-5-fluoro-8-hydroxy-3-methyl-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-5-((2,4-dichlorobenzyl)carbamoyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline1-oxide;(5S,8S)-5-fluoro-8-hydroxy-8-methyl-N-(2,3,4-trifluorobenzyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-4-fluorobenzyl)-5-fluoro-8-hydroxy-8-methyl-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-N-(2-chloro-4-fluorobenzyl)-5-fluoro-8-hydroxy-8-methyl-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-4-fluoro-6-(hydroxymethyl)benzyl)-5-fluoro-8-hydroxy-8-methyl-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2,4-difluorobenzyl)-5-fluoro-8-hydroxy-8-methyl-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(4-chloro-2-fluorobenzyl)-5-fluoro-8-hydroxy-8-methyl-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-4,6-difluorobenzyl)-5-fluoro-8-hydroxy-8-methyl-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(4-chloro-2,3-difluorobenzyl)-5-fluoro-8-hydroxy-8-methyl-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(4-chloro-2,6-difluorobenzyl)-5-fluoro-8-hydroxy-8-methyl-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-((S)-1-(2-chloro-4-fluorophenyl)ethyl)-5-fluoro-8-hydroxy-8-methyl-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-((3,5-dichloropyridin-2-yl)methyl)-5-fluoro-8-hydroxy-8-methyl-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-((trans)-2-(2,4-dichlorophenyl)cyclopropyl)-5-fluoro-8-hydroxy-8-methyl-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-N-(2,4-dichlorobenzyl)-5-fluoro-8-hydroxy-8-(((2-hydroxyethyl)(methyl)amino)methyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8S)-N-(2,4-dichlorobenzyl)-5-fluoro-8-hydroxy-8-(((2-hydroxyethyl)(methyl)amino)methyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8S)-N-(2,4-dichlorobenzyl)-5-fluoro-8-hydroxy-8-((3-hydroxyazetidin-1-yl)methyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-8-(cyanomethyl)-N-(2,4-dichlorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-N-(2-chloro-4-fluorobenzyl)-8-(cyanomethyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-4-fluorobenzyl)-8-(cyanomethyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-N-(2-chloro-4-fluoro-6-(hydroxymethyl)benzyl)-8-(cyanomethyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2,4-dichlorobenzyl)-5-fluoro-8-(fluoromethyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-4-fluorobenzyl)-5-fluoro-8-(fluoromethyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(2R,5'S)-N-(2,4-dichlorobenzyl)-5′-fluoro-4-methyl-6′,7′-dihydro-5′H-spiro[morpholine-2,8′-quinoline]-5′-carboxamide;(5S,5'S)-N-(2,4-dichlorobenzyl)-5′-fluoro-2-oxo-6′,7′-dihydro-5′H-spiro[oxazolidine-5,8′-quinoline]-5′-carboxamide;(5R,5'S)-N-(2,4-dichlorobenzyl)-5′-fluoro-2-oxo-6′,7′-dihydro-5′H-spiro[oxazolidine-5,8′-quinoline]-5′-carboxamide;(2S,5′R)-N-(2,4-dichlorobenzyl)-5′-fluoro-5-oxo-6′,7′-dihydro-5′H-spiro[morpholine-2,8′-quinoline]-5′-carboxamide;(2S,5'S)-N-(2,4-dichlorobenzyl)-5′-fluoro-5-oxo-6′,7′-dihydro-5′H-spiro[morpholine-2,8′-quinoline]-5′-carboxamide;(2R,5'S)-N-(2,4-dichlorobenzyl)-5′-fluoro-5-oxo-6′,7′-dihydro-5′H-spiro[morpholine-2,8′-quinoline]-5′-carboxamide;(5S,8S)-N-(2-chloro-4-fluorobenzyl)-5-fluoro-8-hydroxy-8-((methylsulfinyl)methy)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-4-fluorobenzyl)-5-fluoro-8-hydroxy-8-((methylsulfonyl)methy)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2,4-dichlorobenzyl)-5-fluoro-8-hydroxy-8-(((2-hydroxyethyl)sulfonyl)methyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-4-fluorobenzyl)-5-fluoro-8-hydroxy-8-(((2-hydroxyethyl)sulfonyl)methyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8R)-N-(2,4-dichlorobenzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5R,8S)-N-(2,4-dichlorobenzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2,4-dichlorobenzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-N-(2,4-dichlorobenzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-4-fluorobenzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-N-(2-chloro-4-fluorobenzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-N-(2,3,4-trifluorobenzyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-N-(2,3,4-trifluorobenzyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2,4-dichloro-6-fluorobenzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-N-(2,4-dichloro-6-fluorobenzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-3,4-difluorobenzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-N-(2-chloro-3,4-difluorobenzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(4-chloro-2-fluorobenzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-N-(4-chloro-2-fluorobenzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2,4-dichloro-6-(hydroxymethyl)benzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-4-fluoro-6-(hydroxymethyl)benzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2,4-difluorobenzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2,4-dichloro-3-fluorobenzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2-chloro-4,6-difluorobenzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(4-chloro-2,3-difluorobenzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(3-chloro-2,4-difluorobenzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(4-chloro-2,6-difluorobenzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-((R)-1-(2,4-dichlorophenyl)ethyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-((R)-1-(2-chloro-4-fluorophenyl)ethyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8R)-N-((R)-1-(2-chloro-4-fluorophenyl)ethyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-((3,5-dichloropyridin-2-yl)methyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-((trans)-2-(2,4-dichlorophenyl)cyclopropyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-5-fluoro-8-methoxy-N-(2,4,6-trifluorobenzyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(2,4-difluorobenzyl)-5-fluoro-8-methoxy-5,6,7,8-tetrahydroquinoline-5-carboxamide;(5S,8S)-N-(4-chloro-2-fluorobenzyl)-5-fluoro-8-(2-hydroxyethoxy)-5,6,7,8-tetrahydroquinoline-5-carboxamideand(5S,8S)-N-(2,4-difluorobenzyl)-5-fluoro-8-(2-hydroxyethoxy)-5,6,7,8-tetrahydroquinoline-5-carboxamide.23. A compound represented by the following formula (L-a) or apharmaceutically acceptable salt thereof:

wherein: R³ is independently selected from the group consisting of: (1)hydrogen, (2) halogen, (3) C₁₋₆ alkyl and (4) —O—C₁₋₆ alkyl; p is 0, 1,2 or 3; when p is 2 or 3, each R³ is the same or different; R¹⁶ isselected from the group consisting of: (1) CN and (2) —CO₂R¹⁸; R¹⁷ isselected from the group consisting of: (1) fluoro and (2) hydroxyl; or,R¹⁶ may form ═O with R¹⁷; R¹⁸ is selected from the group consisting of:(1) hydrogen and (2) C₁₋₆ alkyl or a compound represented by thefollowing formula (L-b) or a pharmaceutically acceptable salt thereof:

wherein: R³ is independently selected from the group consisting of: (1)hydrogen, (2) halogen, (3) C₁₋₆ alkyl and (4) —O—C₁₋₆ alkyl; p is 0, 1,2 or 3; when p is 2 or 3, each R³ is the same or different; R⁴ isselected from the group consisting of: (1) hydrogen, (2) halogen and (3)hydroxyl.
 24. A method for the treatment of a condition or disordermediated by P2X7 receptor antagonistic activity in a mammalian subject,including a human, which comprises administering to a mammal in need ofsuch treatment a therapeutically effective amount of a compounddescribed in claim 17 or a pharmaceutically acceptable salt thereof or aprodrug thereof.
 25. The method as described in claim 24, wherein thecondition or disorder is selected from the group consisting of: diseasesof the autoimmune and inflammatory system; diseases of the nervous andneuro-immune system; diseases involved with, and without,neuroinflammation of the Central Nervous System (CNS); diseases of thecardiovascular, metabolic, gastrointestinal and urogenital systems;skeletal disorders, diseases involving the secretory function ofexocrine glands and glaucoma, Glomerulonephritis, Chaga's Disease,chlamydia, neuroblastoma, Tuberculosis, Polycystic Kidney Disease,cancer, and acne; and combinations thereof.
 26. A pharmaceuticalcomposition comprising a compound or a pharmaceutically acceptable saltthereof or a prodrug thereof, as described in claim 17, and apharmaceutically acceptable carrier.
 27. The pharmaceutical compositionas described in claim 26, further comprising another pharmacologicallyactive agent.
 28. A process for preparing a pharmaceutical composition,wherein the process comprises mixing a compound described in claim 17 ora pharmaceutically acceptable salt thereof or a prodrug thereof and apharmaceutically acceptable carrier or excipient.